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Tanaka Y, Hanada T, Amano T, Takahashi A, Deguchi M, Yamanaka H, Tsuji S, Murakami T. Optimizing treatment efficacy and fertility preservation in patients undergoing hematopoietic stem cell transplantation: A narrative review of ovarian shielding with total-body irradiation or treosulfan-based conditioning regimens. Reprod Med Biol 2025; 24:e12648. [PMID: 40255903 PMCID: PMC12006034 DOI: 10.1002/rmb2.12648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Accepted: 04/04/2025] [Indexed: 04/22/2025] Open
Abstract
Background Pediatric and adolescent/young adult (AYA) patients with hematologic malignancies often require hematopoietic stem cell transplantation (HSCT) using conditioning regimens that pose high risks for gonadal toxicity. Traditional protocols, including total body irradiation (TBI) and busulfan-based regimens, can impair fertility. This review explores the potential of gonadal shielding during TBI and treosulfan-based conditioning as strategies to optimize treatment efficacy while preserving fertility. Methods A PubMed search up to February 2025 was performed for English, peer-reviewed articles on hematologic malignancies, HSCT, shielding, and treosulfan. Studies on oncologic outcomes and fertility in pediatric and AYA patients were included. Main Findings Ovarian shielding during myeloablative conditioning with TBI effectively reduces ovarian radiation exposure, resulting in improved menstrual recovery and hormone profiles. A treosulfan-based regimen demonstrated higher antitumor activity than a reduced-intensity busulfan-based regimen in randomized controlled trials. In a retrospective analysis, the treosulfan-based regimen exhibited lower gonadal toxicity than the busulfan-based regimen, although careful attention must be paid to dosing settings of the regimens. Conclusion Ovarian shielding during TBI and a treosulfan-based regimen hold the potential to preserve the reproductive capacity of patients undergoing HSCT. Future clinical studies that appropriately assess both oncological outcomes and fertility are needed to validate these findings.
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Affiliation(s)
- Yuji Tanaka
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Tetsuro Hanada
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Tsukuru Amano
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Akimasa Takahashi
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Mari Deguchi
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Hiroyuki Yamanaka
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Shunichiro Tsuji
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
| | - Takashi Murakami
- Department of Obstetrics and GynaecologyShiga University of Medical ScienceOtsuShigaJapan
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2
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Su GA, Wadsworth OJ, Muller HS, Archer WR, Hetts SW, Schulz MD. Polymer-nucleobase composites for chemotherapy drug capture. J Mater Chem B 2023; 11:8449-8455. [PMID: 37580990 DOI: 10.1039/d3tb00819c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/16/2023]
Abstract
Intravenous chemotherapy (e.g., doxorubicin (DOX)) is standard treatment for many cancers but also leads to side effects due to off-target toxicity. To address this challenge, devices for removing off-target chemotherapy agents from the bloodstream have been developed, but the efficacy of such devices relies on the ability of the underlying materials to specifically sequester small-molecule drugs. Anion-exchange materials, genomic DNA, and DNA-functionalized iron oxide particles have all been explored as drug-capture materials, but cost, specificity, batch-to-batch variation, and immunogenicity concerns persist as challenges. Here, we report a new class of fully synthetic drug-capture materials. We copolymerized methacrylic acid and ethylene glycol dimethacrylate in the presence of several nucleobases and derivatives (adenine, cytosine, xanthine, and thymine) to yield a crosslinked resin with nucleobases integrated into the material. These materials demonstrated effective DOX capture: up to 27 mg of DOX per g of material over 20 minutes from a phosphate-buffered saline solution with an initial concentration of 0.05 mg mL-1 of DOX. These materials use only the individual nucleobases for DOX capture and exhibit competitive capture efficacy compared to previous materials that used genomic DNA, making this approach more cost-effective and reducing potential immunological concerns.
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Affiliation(s)
- Gillian A Su
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Ophelia J Wadsworth
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA.
| | - H Suzanne Muller
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA.
| | - William R Archer
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA.
| | - Steven W Hetts
- Departments of Radiology, Biomedical Imaging, and Neurological Surgery, University of California, San Francisco, CA 94143-0628, USA
| | - Michael D Schulz
- Department of Chemistry and Macromolecules Innovation Institute, Virginia Tech, Blacksburg, VA 24061, USA.
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3
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Porfyriou E, Letsa S, Kosmas C. Hematopoietic stem cell mobilization strategies to support high-dose chemotherapy: A focus on relapsed/refractory germ cell tumors. World J Clin Oncol 2021; 12:746-766. [PMID: 34631440 PMCID: PMC8479351 DOI: 10.5306/wjco.v12.i9.746] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 06/19/2021] [Accepted: 07/30/2021] [Indexed: 02/06/2023] Open
Abstract
High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors (GCTs) who failed to be cured by conventional chemotherapy. Hematopoietic stem cells (HSCs) collected from the peripheral blood, after appropriate pharmacologic mobilization, have largely replaced bone marrow as the principal source of HSCs in transplants. As it is currently common practice to perform tandem or multiple sequential cycles of HDCT, it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure. Moreover, the CD34+ cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment, with patients who receive > 2 × 106 CD34+ cells/kg having consistent, rapid, and sustained hematopoietic recovery. However, many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy, which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy. Therefore, alternative strategies that use novel agents in combination with traditional mobilizing regimens are required. Herein, after an overview of the mechanisms of HSCs mobilization, we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs, and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.
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Affiliation(s)
- Eleni Porfyriou
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
| | - Sylvia Letsa
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
| | - Christos Kosmas
- Department of Medical Oncology and Hematopoietic Cell Transplant Unit, “Metaxa” Cancer Hospital, Piraeus 18537, Greece
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4
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Yee DW, Hetts SW, Greer JR. 3D-Printed Drug Capture Materials Based on Genomic DNA Coatings. ACS APPLIED MATERIALS & INTERFACES 2021; 13:41424-41434. [PMID: 34124877 PMCID: PMC11232429 DOI: 10.1021/acsami.1c05209] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
The toxic side effects of chemotherapy have long limited its efficacy, prompting expensive and long-drawn efforts to develop more targeted cancer therapeutics. An alternative approach to mitigate off-target toxicity is to develop a device that can sequester chemotherapeutic agents from the veins that drain the target organ before they enter systemic circulation. This effectively localizes the chemotherapy to the target organ, minimizing any hazardous side effects. 3D printing is ideal for fabricating these devices, as the geometric control afforded allows us to precisely dictate its hemodynamic performance in vivo. However, the existing materials compatible with 3D printing do not have drug-binding capabilities. Here, we report the stable coating of genomic DNA on a 3D-printed structure for the capture of doxorubicin. Genomic DNA is an effective chemotherapeutic-agent capture material due to the intrinsic DNA-targeting mechanism of action of these drugs. Stable DNA coatings were achieved through a combination of electrostatic interactions and ultraviolet C (UVC, 254 nm) cross-linking. These UVC cross-linked DNA coatings were extremely stable-leaching on average 100 pg of genomic DNA per mm2 of 3D-printed structure over a period of 30 min. In vitro studies of these materials in phosphate buffered saline and human serum demonstrated that they were able to capture, on average, 72 and 60 ng of doxorubicin per mm2 of structure, respectively. The stability and efficacy of these genomic DNA-coated 3D-printed materials represent a significant step forward towards the translation of these devices to clinical applications for the potential improvement of chemotherapy treatment.
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Affiliation(s)
- Daryl W Yee
- Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California 91125, United States
| | - Steven W Hetts
- Department of Radiology and Biomedical Imaging, University of California - San Francisco, San Francisco, California 94107, United States
| | - Julia R Greer
- Division of Engineering and Applied Science, California Institute of Technology, Pasadena, California 91125, United States
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5
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Maani N, Diorio TC, Hetts SW, Rayz VL. Computational modeling of drug transport and mixing in the chemofilter device: enhancing the removal of chemotherapeutics from circulation. Biomech Model Mechanobiol 2020; 19:1865-1877. [PMID: 32166531 PMCID: PMC10821812 DOI: 10.1007/s10237-020-01313-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Accepted: 02/17/2020] [Indexed: 02/06/2023]
Abstract
Intra-arterial chemotherapy (IAC) is the preferred treatment for non-resectable hepatocellular carcinoma. A large fraction of IAC drugs, e.g., Doxorubicin, pass into systemic circulation, causing cardiac toxicity and reducing effectiveness of the procedure. These excessive drugs can be captured by the Chemofilter-a 3D-printable, catheter-based device deployed in a vein downstream of the liver during IAC. In this study, alternative configurations of the Chemofilter device were compared by evaluating their hemodynamic and filtration performance through multiphysics computational fluid dynamics simulations. Two designs were evaluated, a honeycomb-like structure of parallel hexagonal channels (honeycomb Chemofilter) and a cubic lattice of struts (strutted Chemofilter). The computationally optimized Chemofilter design contains three honeycomb stages, each perforated and twisted, which improved Doxorubicin adsorption by 44.6% compared to a straight channel design. The multiphysics simulations predicted an overall 66.8% decrease in concentration with a 2.9 mm-Hg pressure drop across the optimized device compared to a 50% concentration decrease observed during in-vivo experiments conducted with the strutted Chemofilter. The Doxorubicin transport simulations demonstrated the effectiveness of the Chemofilter in removing excessive drugs from circulation while minimizing pressure drop and eliminating flow stagnation regions prone to thrombosis. These results demonstrate the value of the multiphysics modeling approach in device optimization and experimental burden reduction.
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Affiliation(s)
- Nazanin Maani
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Tyler C. Diorio
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
| | - Steven W. Hetts
- Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA
| | - Vitaliy L. Rayz
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN, USA
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6
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Koonrungsesomboon N, Ngamphaiboon N, Townamchai N, Teeyakasem P, Charoentum C, Charoenkwan P, Natesirinilkul R, Sathitsamitphong L, Ativitavas T, Chaiyawat P, Klangjorhor J, Hongeng S, Pruksakorn D. Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial. BMC Cancer 2020; 20:268. [PMID: 32228535 PMCID: PMC7106788 DOI: 10.1186/s12885-020-06751-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 03/12/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Clinical outcomes of patients with osteosarcoma remain unsatisfactory, with little improvement in a 5-year overall survival over the past three decades. There is a substantial need for further research and development to identify and develop more efficacious agents/regimens in order to improve clinical outcomes of patients for whom the prognosis is unfavorable. Recently, mycophenolate mofetil, a prodrug of mycophenolic acid, has been found to have anticancer activity against osteosarcoma in both in vitro and animal experiments, so that further investigation in humans is warranted. METHODS A total of 27 patients with high-grade locally advanced or metastatic osteosarcoma will be enrolled into this phase II, multi-center, open-label, single-arm, two-stage clinical trial. The main objectives of this study are to determine the efficacy and safety of mycophenolate mofetil in the patients. The primary endpoint is progression-free survival at 16 weeks; the secondary endpoints include progression-free survival, overall survival, overall response rate, safety parameters, pharmacokinetic parameters, biomarkers, pain score, and quality of life. Mycophenolate mofetil at the initial dose of 5 g/day or lower will be administered for 4 cycles (28 days/cycle) or until disease progression or unacceptable toxicity. The dose of mycophenolate mofetil may be reduced by 1-2 g/day or withheld for some Grade 3 or Grade 4 toxicities whenever clinically needed. The duration of study participation is approximately 4-5 months, with a minimum of 12 study visits. If mycophenolate mofetil proves beneficial to some patients, as evidenced by stable disease or partial response at 16 weeks, administration of mycophenolate mofetil will continue in the extension period. DISCUSSION This trial is the first step in the translation of therapeutic potential of mycophenolate mofetil emerging from in vitro and animal studies into the clinical domain. It is designed to assess the efficacy and safety of mycophenolate mofetil in patients with high-grade locally advanced or metastatic osteosarcoma. The results will provide important information about whether or not mycophenolate mofetil is worth further development. TRIAL REGISTRATION This trial was prospectively registered on Thai Clinical Trials Registry (registration number: TCTR20190701001). The posted information will be updated as needed to reflect protocol amendments and study progress.
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Affiliation(s)
- Nut Koonrungsesomboon
- Department of Pharmacology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Muscoloskeletal Science and Translational Research (MSTR) Center, Chiang Mai University, Chiang Mai, Thailand
| | - Nuttapong Ngamphaiboon
- Department of Internal Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Nakhon Pathom, Thailand
| | - Natavudh Townamchai
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Pimpisa Teeyakasem
- Muscoloskeletal Science and Translational Research (MSTR) Center, Chiang Mai University, Chiang Mai, Thailand
| | - Chaiyut Charoentum
- Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Pimlak Charoenkwan
- Departmnet of Pediatrics, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | | | | | - Touch Ativitavas
- Department of Internal Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Nakhon Pathom, Thailand
| | - Parunya Chaiyawat
- Muscoloskeletal Science and Translational Research (MSTR) Center, Chiang Mai University, Chiang Mai, Thailand
| | - Jeerawan Klangjorhor
- Muscoloskeletal Science and Translational Research (MSTR) Center, Chiang Mai University, Chiang Mai, Thailand
| | - Suradej Hongeng
- Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Nakhon Pathom, Thailand
| | - Dumnoensun Pruksakorn
- Muscoloskeletal Science and Translational Research (MSTR) Center, Chiang Mai University, Chiang Mai, Thailand.
- Department of Orthopedics, Faculty of Medicine, Chiang Mai University, 110 Intawaroros, Sriphoom, Muang, Chiang Mai, 50200, Thailand.
- Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand.
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7
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Martin JH, Dimmitt S. The rationale of dose-response curves in selecting cancer drug dosing. Br J Clin Pharmacol 2019; 85:2198-2204. [PMID: 31077412 PMCID: PMC6783605 DOI: 10.1111/bcp.13979] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/11/2019] [Accepted: 04/15/2019] [Indexed: 12/21/2022] Open
Abstract
Drug development for cancer chemotherapy has an interesting history. A mix of serendipity, animal, cell line, and standard pharmacological principles of dose, dose-response, dose-concentration, dose intensity and combination therapies have been used to develop optimal dosing schedules. However in practice, significant gaps in the translation of preclinical to clinical dosing schedules persist, and clinical development has instead moved to new drug development. A older chemotherapies are still the backbone of most solid tumour schedules, therapeutic drug monitoring has emerged as a method for optimising the dose for individual patients.
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Affiliation(s)
| | - Simon Dimmitt
- University of Newcastle. New South WalesAustralia
- University of Western AustraliaCrawleyPerthAustralia
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8
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Synergistic Cytotoxicity of Renieramycin M and Doxorubicin in MCF-7 Breast Cancer Cells. Mar Drugs 2019; 17:md17090536. [PMID: 31527453 PMCID: PMC6780817 DOI: 10.3390/md17090536] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 08/05/2019] [Accepted: 08/07/2019] [Indexed: 12/17/2022] Open
Abstract
Renieramycin M (RM) is a KCN-stabilized tetrahydroisoquinoline purified from the blue sponge Xestospongia sp., with nanomolar IC50s against several cancer cell lines. Our goal is to evaluate its combination effects with doxorubicin (DOX) in estrogen receptor positive MCF-7 breast cancer cells. MCF-7 cells were treated simultaneously or sequentially with various combination ratios of RM and DOX for 72 h. Cell viability was determined using the MTT assay. Synergism or antagonism was determined using curve-shift analysis, combination index method and isobologram analysis. Synergism was observed with pharmacologically achievable concentrations of DOX when administered simultaneously, but not sequentially. The IC95 values of RM and DOX after combination were reduced by up to four-fold and eight-fold, respectively. To gain insights on the mechanism of synergy, real-time profiling, cell cycle analysis, apoptosis assays, and transcriptome analysis were conducted. The combination treatment displayed a similar profile with DNA-damaging agents and induced a greater and faster cell killing. The combination treatment also showed an increase in apoptosis. DOX induced S and G2/M arrest while RM did not induce significant changes in the cell cycle. DNA replication and repair genes were downregulated commonly by RM and DOX. p53 signaling and cell cycle checkpoints were regulated by DOX while ErbB/PI3K-Akt, integrin and focal adhesion signaling were regulated by RM upon combination. Genes involved in cytochrome C release and interferon gamma signaling were regulated specifically in the combination treatment. This study serves as a basis for in vivo studies and provides a rationale for using RM in combination with other anticancer drugs.
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9
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Kwak CH, Lee JH, Kim EY, Han CW, Kim KJ, Lee H, Cho M, Jang SB, Kim CH, Chung TW, Ha KT. Huzhangoside A Suppresses Tumor Growth through Inhibition of Pyruvate Dehydrogenase Kinase Activity. Cancers (Basel) 2019; 11:712. [PMID: 31126094 PMCID: PMC6562422 DOI: 10.3390/cancers11050712] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Revised: 05/17/2019] [Accepted: 05/18/2019] [Indexed: 12/20/2022] Open
Abstract
Aerobic glycolysis is one of the important metabolic characteristics of many malignant tumors. Pyruvate dehydrogenase kinase (PDHK) plays a key role in aerobic glycolysis by phosphorylating the E1α subunit of pyruvate dehydrogenase (PDH). Hence, PDHK has been recognized as a molecular target for cancer treatment. Here, we report that huzhangoside A (Hu.A), a triterpenoid glycoside compound isolated from several plants of the Anemone genus, acts as a novel PDHK inhibitor. Hu.A was found to decrease the cell viability of human breast cancer MDA-MB-231, hepatocellular carcinoma Hep3B, colon cancer HT-29, DLD-1, and murine lewis lung carcinoma LLC cell lines. The activity of PDHK1 was decreased by Hu.A in both in vitro assays and in vivo assays in DLD-1 cells. Hu.A significantly increased the oxygen consumption and decreased the secretory lactate levels in DLD-1 cells. In addition, Hu.A interacted with the ATP-binding pocket of PDHK1 without affecting the interaction of PDHK1 and pyruvate dehydrogenase complex (PDC) subunits. Furthermore, Hu.A significantly induced mitochondrial reactive oxygen species (ROS) and depolarized the mitochondrial membrane potential in DLD-1 cells. Consistently, when Hu.A was intraperitoneally injected into LLC allograft mice, the tumor growth was significantly decreased. In conclusion, Hu.A suppressed the growth of tumors in both in vitro and in vivo models via inhibition of PDHK activity.
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Affiliation(s)
- Choong-Hwan Kwak
- Korean Medical Research Center for Healthy Aging, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
| | - Jung-Hee Lee
- Korean Medical Research Center for Healthy Aging, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
| | - Eun-Yeong Kim
- Korean Medical Research Center for Healthy Aging, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
| | - Chang Woo Han
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Geumjeong-gu, Busan 46241, Korea.
| | - Keuk-Jun Kim
- Department of Clinical Pathology, TaeKyeung University, Gyeongsan 38547, Korea.
| | - Hanna Lee
- National Development Institute of Korean Medicine, Gyeongsan, Gyeongsanabuk-do 38540, Korea.
| | - MyoungLae Cho
- National Development Institute of Korean Medicine, Gyeongsan, Gyeongsanabuk-do 38540, Korea.
| | - Se Bok Jang
- Department of Molecular Biology, College of Natural Sciences, Pusan National University, Geumjeong-gu, Busan 46241, Korea.
| | - Cheorl-Ho Kim
- Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-do 16419, Korea.
| | - Tae-Wook Chung
- Korean Medical Research Center for Healthy Aging, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
| | - Ki-Tae Ha
- Korean Medical Research Center for Healthy Aging, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Korea.
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10
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Casey DL, Wexler LH, Wolden SL. Worse Outcomes for Head and Neck Rhabdomyosarcoma Secondary to Reduced-Dose Cyclophosphamide. Int J Radiat Oncol Biol Phys 2019; 103:1151-1157. [PMID: 30508617 PMCID: PMC6441953 DOI: 10.1016/j.ijrobp.2018.11.049] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Revised: 11/21/2018] [Accepted: 11/26/2018] [Indexed: 12/28/2022]
Abstract
PURPOSE Recent trends, including the use of proton therapy and administration of reduced doses of cyclophosphamide, have been adapted in head and neck (HN) rhabdomyosarcoma (RMS) to reduce late morbidity. Our primary goal was to analyze local control and survival outcomes after photon versus proton irradiation in pediatric patients with HN-RMS, with the secondary goal of analyzing the effect of cyclophosphamide dose on disease outcomes. METHODS AND MATERIALS This single-institution cohort study comprised 76 pediatric HN-RMS patients treated with definitive chemoradiation from 2000 to 2018. Fifty-one patients (67%) received intensity modulated photon radiation therapy, and 25 (33%) received proton therapy. RESULTS Local failure (LF) at 2 years was 12.5% for parameningeal RMS and 0% for orbital RMS and other head and neck sites (P = .24). Patients treated with protons were more likely to have received reduced-dose cyclophosphamide (P < .0001). The 2-year LF was 7.9% in the intensity modulated photon radiation therapy cohort versus 14.6% in the proton cohort (P = .07), with no difference in survival outcomes. Cumulative cyclophosphamide dose was significantly associated with 2-year LF: 0% for cumulative dose of >20 g/m2 versus 15.3% for ≤20 g/m2 (P = .04). In parameningeal RMS patients (n = 59), both cumulative cyclophosphamide dose and dose intensity were associated with LF (P = .01). There was a trend toward worse event-free survival for parameningeal RMS patients who received reduced-dose-intensity cyclophosphamide (59.2% vs 70.6%, P = .11). CONCLUSIONS Both dose-intensity and cumulative cyclophosphamide dose seem to play an important role in achieving local control for HN-RMS patients treated with either protons or photons. Longer follow-up is needed to further assess disease outcomes with proton therapy.
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MESH Headings
- Adolescent
- Antineoplastic Agents, Alkylating/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Child
- Child, Preschool
- Combined Modality Therapy/methods
- Cyclophosphamide/administration & dosage
- Female
- Head and Neck Neoplasms/drug therapy
- Head and Neck Neoplasms/mortality
- Head and Neck Neoplasms/radiotherapy
- Head and Neck Neoplasms/surgery
- Humans
- Male
- Neoplasm Recurrence, Local
- Proton Therapy/adverse effects
- Proton Therapy/methods
- Proton Therapy/statistics & numerical data
- Radiotherapy Dosage
- Radiotherapy, Adjuvant/methods
- Radiotherapy, Intensity-Modulated/adverse effects
- Radiotherapy, Intensity-Modulated/methods
- Radiotherapy, Intensity-Modulated/statistics & numerical data
- Relative Biological Effectiveness
- Rhabdomyosarcoma, Alveolar/drug therapy
- Rhabdomyosarcoma, Alveolar/mortality
- Rhabdomyosarcoma, Alveolar/radiotherapy
- Rhabdomyosarcoma, Alveolar/surgery
- Rhabdomyosarcoma, Embryonal/drug therapy
- Rhabdomyosarcoma, Embryonal/mortality
- Rhabdomyosarcoma, Embryonal/radiotherapy
- Rhabdomyosarcoma, Embryonal/surgery
- Treatment Outcome
- Young Adult
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Affiliation(s)
- Dana L Casey
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Leonard H Wexler
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Suzanne L Wolden
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
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11
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Oh HJ, Aboian MS, Yi MYJ, Maslyn JA, Loo WS, Jiang X, Parkinson DY, Wilson MW, Moore T, Yee CR, Robbins GR, Barth FM, DeSimone JM, Hetts SW, Balsara NP. 3D Printed Absorber for Capturing Chemotherapy Drugs before They Spread through the Body. ACS CENTRAL SCIENCE 2019; 5:419-427. [PMID: 30937369 PMCID: PMC6439445 DOI: 10.1021/acscentsci.8b00700] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Indexed: 05/05/2023]
Abstract
Despite efforts to develop increasingly targeted and personalized cancer therapeutics, dosing of drugs in cancer chemotherapy is limited by systemic toxic side effects. We have designed, built, and deployed porous absorbers for capturing chemotherapy drugs from the bloodstream after these drugs have had their effect on a tumor, but before they are released into the body where they can cause hazardous side effects. The support structure of the absorbers was built using 3D printing technology. This structure was coated with a nanostructured block copolymer with outer blocks that anchor the polymer chains to the 3D printed support structure and a middle block that has an affinity for the drug. The middle block is polystyrenesulfonate which binds to doxorubicin, a widely used and effective chemotherapy drug with significant toxic side effects. The absorbers are designed for deployment during chemotherapy using minimally invasive image-guided endovascular surgical procedures. We show that the introduction of the absorbers into the blood of swine models enables the capture of 64 ± 6% of the administered drug (doxorubicin) without any immediate adverse effects. Problems related to blood clots, vein wall dissection, and other biocompatibility issues were not observed. This development represents a significant step forward in minimizing toxic side effects of chemotherapy.
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Affiliation(s)
- Hee Jeung Oh
- Department
of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
| | - Mariam S. Aboian
- Department
of Radiology, School of Medicine, University
of California, San Francisco, California 94110, United States
| | - Michael Y. J. Yi
- Department
of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
| | - Jacqueline A. Maslyn
- Department
of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
- Energy Storage and Distributed
Resources Division, Joint Center for Energy Storage Research
(JCESR), Materials Sciences Division, Advanced Light Source Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Whitney S. Loo
- Department
of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
| | - Xi Jiang
- Energy Storage and Distributed
Resources Division, Joint Center for Energy Storage Research
(JCESR), Materials Sciences Division, Advanced Light Source Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Dilworth Y. Parkinson
- Energy Storage and Distributed
Resources Division, Joint Center for Energy Storage Research
(JCESR), Materials Sciences Division, Advanced Light Source Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
| | - Mark W. Wilson
- Department
of Radiology, School of Medicine, University
of California, San Francisco, California 94110, United States
| | - Terilyn Moore
- Department
of Radiology, School of Medicine, University
of California, San Francisco, California 94110, United States
| | - Colin R. Yee
- Department
of Radiology, School of Medicine, University
of California, San Francisco, California 94110, United States
| | - Gregory R. Robbins
- Carbon,
Inc., 1089 Mills Way, Redwood City, California 94063, United States
| | - Florian M. Barth
- Carbon,
Inc., 1089 Mills Way, Redwood City, California 94063, United States
| | - Joseph M. DeSimone
- Carbon,
Inc., 1089 Mills Way, Redwood City, California 94063, United States
- Department
of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599, United States
- Department
of Chemical and Biomolecular Engineering, North Carolina State University, Raleigh, North Carolina 27695, United States
| | - Steven W. Hetts
- Department
of Radiology, School of Medicine, University
of California, San Francisco, California 94110, United States
| | - Nitash P. Balsara
- Department
of Chemical and Biomolecular Engineering, University of California, Berkeley, California 94720, United States
- Energy Storage and Distributed
Resources Division, Joint Center for Energy Storage Research
(JCESR), Materials Sciences Division, Advanced Light Source Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States
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12
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Song T, Zhang M, Liu P, Xue Z, Fan Y, Zhang Z. Identification of JNK1 as a predicting biomarker for ABT-199 and paclitaxel combination treatment. Biochem Pharmacol 2018; 155:102-109. [PMID: 29953843 DOI: 10.1016/j.bcp.2018.06.019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 06/19/2018] [Indexed: 12/14/2022]
Abstract
Targeting Bcl-2 with ABT-199 (Venetoclax) shows limited single-agent activity against many cancers in both preclinical and clinical investigations. Combination therapies have attracted great attention. The principal purpose of this study was to investigate the mechanism of synergism between ABT-199 and paclitaxel. Moreover, we analyzed the biomarker to identify tumors which are most likely to respond to this combination. We evaluated the effect of this combination in a panel of nine cancer cell lines including cervical cancer, lung cancer, ovarian cancer, lymphoma, leukemia and breast cancer. Combination index (CI) assay showed that four of nine call lines exhibited synergistic respond to ABT-199/paclitaxel combination due to enhanced intrinsic apoptosis. However, paclitaxel-induced Bcl-2 phosphorylation impaired the synergistic effect by impeding the freeing of Bax and Bim by ABT-199 because ABT-199 cannot hit phosphorylated Bcl-2 (pBcl-2). By means of a correlation analysis of JNK level with CI value in combination with overexpressing or silencing JNK protein in cancer cells, we identified basal JNK1 level as a potential biomarker for predicting the level of pBcl-2 upon paclitaxel treatment, and thus for predicting a synergistic response. A cut-off value of 0.37 for relative JNK1 expression level was determined using receiver operating characteristic (ROC) analysis to distinguish between synergistic and non-synergistic response cancers. A more accurate and valid cut-off value for JNK1 will be gained based on a large-scale clinical samples analysis.
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Affiliation(s)
- Ting Song
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China
| | - Minhang Zhang
- School of Life Science and Technology, Dalian University of Technology, Dalian, China
| | - Peng Liu
- School of Life Science and Technology, Dalian University of Technology, Dalian, China
| | - Zhenyu Xue
- School of Innovation Experiment, Dalian University of Technology, Dalian, China
| | - Yudan Fan
- School of Life Science and Technology, Dalian University of Technology, Dalian, China
| | - Zhichao Zhang
- State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
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13
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Wyatt BN, Arnold LA, St Maurice M. A high-throughput screening assay for pyruvate carboxylase. Anal Biochem 2018; 550:90-98. [PMID: 29655770 DOI: 10.1016/j.ab.2018.04.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 04/09/2018] [Accepted: 04/11/2018] [Indexed: 01/20/2023]
Abstract
Pyruvate carboxylase (PC) catalyzes the conversion of pyruvate to oxaloacetate (OAA), an important metabolic reaction in a wide range of organisms. Small molecules directed against PC would enable detailed studies on the metabolic role of this enzyme and would have the potential to be developed into pharmacological agents. Currently, specific and potent small molecule regulators of PC are unavailable. To assist in efforts to find, develop, and characterize small molecule effectors of PC, a novel fixed-time assay has been developed based on the reaction of OAA with the diazonium salt, Fast Violet B (FVB), which produces a colored adduct with an absorbance maximum at 530 nm. This fixed time assay is reproducible, sensitive and responsive to known effectors of Rhizobium etli PC, Staphylococcus aureus PC, and Listeria monocytogenes PC, and is highly amenable to high-throughput screening. The assay was validated using a plate uniformity assessment test and a pilot screen of a library of 1280 compounds. The results indicate that the assay is suitable for screening small molecule libraries to find novel small molecule effectors of PC.
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Affiliation(s)
- Brittney N Wyatt
- Department of Biological Sciences, Marquette University, Milwaukee, WI 53233, USA
| | - Leggy A Arnold
- Department of Chemistry and Biochemistry and Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA
| | - Martin St Maurice
- Department of Biological Sciences, Marquette University, Milwaukee, WI 53233, USA.
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14
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Popovic L, Matovina-Brko G, Popovic M, Petrovic D, Cvetanovic A, Vukojevic J, Jovanovic D. High dose chemotherapy with stem cell support in the treatment of testicular cancer. World J Stem Cells 2015; 7:1222-1232. [PMID: 26730267 PMCID: PMC4691691 DOI: 10.4252/wjsc.v7.i11.1222] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2014] [Revised: 02/23/2015] [Accepted: 11/17/2015] [Indexed: 02/06/2023] Open
Abstract
Testicular germ cell cancer (TGCC) is rare form of malignant disease that occurs mostly in young man between age 15 and 40. The worldwide incidence of TGCC is 1.5 per 100000 man with the highest rates in North Europe. After discovery of cisplatin cure rates of TGCC are very favorable between 90%-95% and unlike most solid tumors, cure rate for metastatic TGCC is around 80%. Metastatic TGCC is usually treated with 3-4 cycles of bleomycin, etoposide, cisplatinum chemotherapy with or without retroperitoneal surgery and cure rates with this approach are between 41% in poor risk group and 92% in good risk group of patients. Cure rates are lower in relapsed and refractory patients and many of them will die from the disease if not cured with first line chemotherapy. High dose chemotherapy (HDCT) approach was used for the first time during the 1980s. Progress in hematology allowed the possibility to keep autologous haematopoietic stem cells alive ex-vivo at very low temperatures and use them to repopulate the bone marrow after sub-lethal dose of intesive myeloablative chemotherapy. Despite the fact that there is no positive randomized study to prove HDCT concept, cure rates in relapsed TGCC are higher after high dose therapy then in historical controls in studies with conventional treatment. Here we review clinical studies in HDCT for TGCC, possibilities of mobilising sufficient number of stem cells and future directions in the treatment of this disease.
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15
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Patel AS, Saeed M, Yee EJ, Yang J, Lam GJ, Losey AD, Lillaney PV, Thorne B, Chin AK, Malik S, Wilson MW, Chen XC, Balsara NP, Hetts SW. Development and Validation of Endovascular Chemotherapy Filter Device for Removing High-Dose Doxorubicin: Preclinical Study. J Med Device 2014; 8:0410081-410088. [PMID: 25653735 DOI: 10.1115/1.4027444] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 04/03/2014] [Indexed: 12/23/2022] Open
Abstract
To develop a novel endovascular chemotherapy filter (CF) able to remove excess drug from the blood during intra-arterial chemotherapy delivery (IAC), thus preventing systemic toxicities and thereby enabling higher dose IAC. A flow circuit containing 2.5 mL of ion-exchange resin was constructed. Phosphate-buffered saline (PBS) containing 50 mg doxorubicin (Dox) was placed in the flow model with the hypothesis that doxorubicin would bind rapidly to resin. To simulate IAC, 50 mg of doxorubicin was infused over 10 min into the flow model containing resin. Similar testing was repeated with porcine serum. Doxorubicin concentrations were measured over 60 min and compared to controls (without resin). Single-pass experiments were also performed. Based on these experiments, an 18F CF was constructed with resin in its tip. In a pilot porcine study, the device was deployed under fluoroscopy. A control hepatic doxorubicin IAC model (no CF placed) was developed in another animal. A second CF device was created with a resin membrane and tested in the infrarenal inferior vena cava (IVC) of a swine. In the PBS model, resin bound 76% of doxorubicin in 10 min, and 92% in 30 min (P < 0.001). During IAC simulation, 64% of doxorubicin bound in 10 min and 96% in 60 min (P < 0.001). On average, 51% of doxorubicin concentration was reduced during each pass in single pass studies. In porcine serum, 52% of doxorubicin bound in 10 min, and 80% in 30 min (P < 0.05). CF device placement and administration of IAC were successful in three animals. No clot was present on the resin within the CF following the in vivo study. The infrarenal IVC swine study demonstrated promising results with up to 85% reduction in peak concentration by the CF device. An endovascular CF device was developed and shown feasible in vitro. An in vivo model was established with promising results supporting high-capacity rapid doxorubicin filtration from the blood that can be further evaluated in future studies.
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Affiliation(s)
- Anand S Patel
- Department of Radiology and Biomedical Imaging, University of California San Francisco , 185 Berry Street, Suite 350, San Francisco, CA 94107-5705 e-mail:
| | - Maythem Saeed
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Erin J Yee
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Jeffrey Yang
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Gregory J Lam
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Aaron D Losey
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Prasheel V Lillaney
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Bradford Thorne
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Albert K Chin
- ChemoFilter, Inc. , 645 Woodstock Road, Hillsborough, CA 94010
| | - Sheena Malik
- ChemoFilter, Inc. , 645 Woodstock Road, Hillsborough, CA 94010
| | - Mark W Wilson
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
| | - Xi C Chen
- Materials Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, CA 94720
| | - Nitash P Balsara
- Materials Sciences Division, Lawrence Berkeley National Laboratory , Berkeley, CA 94720
| | - Steven W Hetts
- Department of Radiology and Biomedical Imaging, University of California San Francisco , San Francisco, CA 94107
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16
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Aljitawi OS, Ganguly S, Abhyankar SH, Ferree M, Marks R, Pipkin JD, McGuirk JP. Phase IIa cross-over study of propylene glycol-free melphalan (LGD-353) and alkeran in multiple myeloma autologous transplantation. Bone Marrow Transplant 2014; 49:1042-5. [DOI: 10.1038/bmt.2014.120] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/27/2014] [Accepted: 04/11/2014] [Indexed: 11/09/2022]
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17
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Krasnov VP, Korolyova MA, Vodovozova EL. Nano-sized melphalan and sarcolysine drug delivery systems: synthesis and prospects of application. RUSSIAN CHEMICAL REVIEWS 2013. [DOI: 10.1070/rc2013v082n08abeh004358] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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18
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Baheti G, McGuire TR, Davda JP, Manouilov KK, Wall D, Gwilt PR, Gordon BB. Clinical pharmacology of etoposide in children undergoing autologous stem cell transplantation for various solid tumours. Xenobiotica 2012; 43:276-82. [PMID: 22931186 DOI: 10.3109/00498254.2012.713530] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
1. The population pharmacokinetics of high-dose etoposide was studied in a group of young children and adolescents. 2. Twenty-six children and adolescent were administered high-dose etoposide as a continuous infusion over 24 h. Etoposide plasma concentration-time data was modelled using NONMEM® 7. The effect of age, weight, serum creatinine (SCr), and gender on pharmacokinetic parameters (CL and V(d)) were determined by a nonlinear mixed effect model. 3. The pharmacokinetics of etoposide based on BSA dosing was best described with a 1-compartment structural model which was parameterised in terms of clearance (CL) and volume of distribution (V(d)). An exponential error model was used to explain intersubject variability and a proportional error model was used to describe residual or intrapatient variability. The final model parameter estimates for the typical (normalised to 70 kg) values of CL and V(d) were 2.31 L/hr and 17.5 L, respectively. The CL and V(d) allometrically increased with weight with the power of 3/4 and 1, respectively. After accounting for weight dependence using the allometric scaling, age, serum creatinine, and gender did not have any influence on model parameters. 4. The results of this children and adolescent population pharmacokinetic study indicates that etoposide pharmacokinetics were influenced by body weight on an allometric basis. The pharmacokinetic parameters CL and V(d) increased with increasing weight similar to BSA.
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Affiliation(s)
- Gautam Baheti
- College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA
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19
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Bernard A, Kimko H, Mital D, Poggesi I. Mathematical modeling of tumor growth and tumor growth inhibition in oncology drug development. Expert Opin Drug Metab Toxicol 2012; 8:1057-69. [PMID: 22632710 DOI: 10.1517/17425255.2012.693480] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Approaches aiming to model the time course of tumor growth and tumor growth inhibition following a therapeutic intervention have recently been proposed for supporting decision making in oncology drug development. When considered in a comprehensive model-based approach, tumor growth can be included in the cascade of quantitative and causally related markers that lead to the prediction of survival, the final clinical response. AREAS COVERED The authors examine articles dealing with the modeling of tumor growth and tumor growth inhibition in both preclinical and clinical settings. In addition, the authors review models describing how pharmacological markers can be used to predict tumor growth and models describing how tumor growth can be linked to survival endpoints. EXPERT OPINION Approaches and success stories of application of model-based drug development centered on tumor growth modeling are growing. It is also apparent that these approaches can answer practical questions on drug development more effectively than that in the past. For modeling purposes, some improvements are still needed related to study design and data quality. Further efforts are needed to encourage the mind shift from a simple description of data to the prediction of untested conditions that modeling approaches allow.
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Affiliation(s)
- Apexa Bernard
- Clinical Pharmacology, Janssen Research and Development, LLC, Raritan, NJ, USA.
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Aljitawi OS, McGuirk JP. Multiple myeloma preparative regimens for high-dose therapy and autologous transplantation: what's new? J Comp Eff Res 2012; 1:57-70. [PMID: 24237297 DOI: 10.2217/cer.11.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
High-dose chemotherapy and autologous stem cell transplantation remains a standard procedure in relatively young and selected older patients with multiple myeloma. High-dose melphalan has remained the chemotherapeutic agent of choice based on earlier prospective randomized trials. Despite investigations involving different combinations of chemotherapeutics, radiation and novel agents with and without melphalan, none of these alternative preparative regimens have demonstrated superiority to high-dose melphalan used as a single agent in multiple published studies. In this article, we review the published literature regarding preparative regimens used in patients with multiple myeloma undergoing autologous stem cell transplantation.
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Affiliation(s)
- Omar S Aljitawi
- The Blood & Marrow Transplant Program, University of Kansas Medical Center, Kansas City, KS, USA; 2330 Shawnee Mission Pkwy, Westwood, KS 66205, USA
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Dingli D, Pacheco JM, Nowakowski GS, Kumar SK, Dispenzieri A, Hayman SR, Lacy MQ, Gastineau DA, Gertz MA. Relationship Between Depth of Response and Outcome in Multiple Myeloma. J Clin Oncol 2007; 25:4933-7. [DOI: 10.1200/jco.2007.11.7879] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose High-dose therapy with autologous stem-cell transplantation (HDT-ASCT) is now almost standard therapy for many patients with multiple myeloma, partly because of higher complete response (CR) rates. Some studies suggest that tandem transplantation gives superior results. The aim of this study was to determine whether the depth of the response to HDT-ASCT leads to an improvement in time to progression (TTP) and overall survival (OS). We hypothesized that patients with CR before HDT-ASCT (BCR) will have their disease burden reduced further and experience a longer TTP and perhaps OS. Patients and Methods All patients who achieved BCR or CR after HDT-ASCT (ACR) were identified. The characteristics and long-term outcome of these patients were evaluated. Results We identified 14 patients with BCR and 103 patients with ACR who were treated in similar fashion. The patients have been followed for more than 6 years, and the median for OS has not been reached (60-month survival, 55% for BCR and 63% for ACR; P = .83). The median TTP was 43 months for BCR and 34 months for ACR (P = .39). Conclusion The depth of the response in myeloma does not necessarily lead to an improvement in TTP and OS. Tumor dynamics considerations show that the yield from sequential cycles of chemotherapy decreases. Patients who achieve CR with the first transplant can be safely observed without jeopardizing OS.
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Affiliation(s)
- David Dingli
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Jorge M. Pacheco
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Grzegorz S. Nowakowski
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Shaji K. Kumar
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Angela Dispenzieri
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Suzanne R. Hayman
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Martha Q. Lacy
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Dennis A. Gastineau
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
| | - Morie A. Gertz
- From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN; and the Centro de Fisica Teórica e Computacional and Departamento de Fisica da Universidade de Lisboa, Portugal
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Dingli D, Pacheco JM, Dispenzieri A, Hayman SR, Kumar SK, Lacy MQ, Gastineau DA, Gertz MA. Serum M-spike and transplant outcome in patients with multiple myeloma. Cancer Sci 2007; 98:1035-40. [PMID: 17488336 PMCID: PMC11159012 DOI: 10.1111/j.1349-7006.2007.00499.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
High dose therapy with autologous stem cell transplantation (HDT-ASCT) has prolonged survival in patients with multiple myeloma. Patients who achieve a complete response (CR) benefit the most from this form of therapy. Thus, achieving a CR is an important goal of therapy and it will be beneficial if the probability of achieving CR can be determined for any patient before transplant. Here we report that pretransplant monoclonal protein level (M-spike) was found to be an important predictor. Thus, we used knowledge of the rate of M-protein production by myeloma cells together with the clearance of the protein to estimate the pretransplant disease burden. We show that the pretransplant disease burden, based on the M-spike, is the only predictor for achieving CR. A simple function that describes this probability is presented. We also provide an estimate of the rate of tumor regrowth in patients who obtain a CR and in patients who only get a partial response with HDT-ASCT. The significant expansion of myeloma cells after HDT-ASCT is clearly evident. Clinical trials must be designed that take into account these kinetic aspects of the disease.
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Affiliation(s)
- David Dingli
- Division of Hematology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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23
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Dingli D, Nowakowski GS, Dispenzieri A, Lacy MQ, Hayman S, Litzow MR, Gastineau DA, Gertz MA. Cyclophosphamide mobilization does not improve outcome in patients receiving stem cell transplantation for multiple myeloma. ACTA ACUST UNITED AC 2006; 6:384-8. [PMID: 16640814 DOI: 10.3816/clm.2006.n.014] [Citation(s) in RCA: 76] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
PURPOSE Patients with multiple myeloma who undergo autologous stem cell transplantation (ASCT) and exhibit a complete response (CR) have a superior overall survival and time to progression (TTP). High-dose cyclophosphamide is often used before ASCT for mobilization of hematopoietic stem cells. We hypothesized that cyclophosphamide might further improve CR rates in patients undergoing ASCT. We searched the Mayo Clinic myeloma transplantation database for patients who had stem cell mobilization with hematopoietic growth factor alone or cyclophosphamide and growth factor. The impact of cyclophosphamide on CR rates and TTP was evaluated. PATIENTS AND METHODS A cohort of 201 patients was identified: 127 mobilized with cyclophosphamide and growth factor and 74 with growth factor alone. There were no statistically significant differences between the 2 cohorts in regard to age, sex, b2-microglobulin level, plasma cell labeling index, cytogenetics, conditioning regimen, or disease status at time of transplantation. RESULTS Complete response rates were 37.4% and 41.3% (P = 0.6115) for patients mobilized with cyclophosphamide combined with growth factor and growth factor alone, respectively, and TTPs were 19.9 months and 20.9 months (P = 0.59). In a multivariate analysis for TTP, cytogenetics and CR rates were the only independent variables (P = 0.0012 and P < 0.0001, respectively). CONCLUSION We conclude that high-dose cyclophosphamide does not increase overall CR rates or improve TTP for patients with myeloma undergoing ASCT.
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Affiliation(s)
- David Dingli
- Mayo Clinic College of Medicine, Rochester, MN 55905, USA
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24
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Alderson RF, Toki BE, Roberge M, Geng W, Basler J, Chin R, Liu A, Ueda R, Hodges D, Escandon E, Chen T, Kanavarioti T, Babé L, Senter PD, Fox JA, Schellenberger V. Characterization of a CC49-based single-chain fragment-beta-lactamase fusion protein for antibody-directed enzyme prodrug therapy (ADEPT). Bioconjug Chem 2006; 17:410-8. [PMID: 16536473 DOI: 10.1021/bc0503521] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
CC49 is a clinically validated antibody with specificity for TAG-72, a carbohydrate epitope that is overexpressed and exposed on the cell surface in a large fraction of solid malignancies. We constructed a single-chain fragment (scFv) based on CC49 and fused it to beta-lactamase (BLA). Following optimization of the scFv domain by combinatorial consensus mutagenesis (CCM) for increased expression and stability, we characterized the protein variant for binding, in vivo pharmacokinetics (PK), and antitumor efficacy. The fusion protein TAB2.5 possessed a similar binding specificity relative to the parent antibody CC49. TAB2.5 also showed prolonged retention (T(1/2) = 36.9 h) in tumor-bearing mice with tumor/plasma ratios of up to 1000. Preliminary evaluation of TAB2.5, in combination with a novel prodrug, GC-Mel, resulted in significant efficacy in a colorectal xenograft tumor model and supports the utility of the protein as an agent for tumor-selective prodrug activation.
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MESH Headings
- Animals
- Antibiotics, Antineoplastic/therapeutic use
- Antibodies, Neoplasm/chemistry
- Antibodies, Neoplasm/genetics
- Antibodies, Neoplasm/metabolism
- Antibodies, Neoplasm/therapeutic use
- Antineoplastic Agents, Alkylating/chemistry
- Antineoplastic Agents, Alkylating/metabolism
- Antineoplastic Agents, Alkylating/therapeutic use
- Antineoplastic Agents, Phytogenic/therapeutic use
- Camptothecin/analogs & derivatives
- Camptothecin/therapeutic use
- Cephalosporins/chemistry
- Cephalosporins/metabolism
- Cephalosporins/therapeutic use
- Colorectal Neoplasms/drug therapy
- Colorectal Neoplasms/metabolism
- Colorectal Neoplasms/pathology
- Doxorubicin/therapeutic use
- Drug Carriers/chemistry
- Drug Carriers/metabolism
- Drug Delivery Systems
- Female
- Humans
- Immunoglobulin Fragments/genetics
- Immunoglobulin Fragments/metabolism
- Immunoglobulin Variable Region/genetics
- Immunoglobulin Variable Region/metabolism
- Irinotecan
- Melphalan/chemistry
- Melphalan/metabolism
- Melphalan/therapeutic use
- Mice
- Mice, Nude
- Molecular Structure
- Neoplasm Transplantation
- Nitrogen Mustard Compounds/chemistry
- Nitrogen Mustard Compounds/metabolism
- Nitrogen Mustard Compounds/therapeutic use
- Prodrugs/chemistry
- Prodrugs/metabolism
- Prodrugs/therapeutic use
- Recombinant Fusion Proteins/chemistry
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
- Recombinant Fusion Proteins/therapeutic use
- beta-Lactamases/chemistry
- beta-Lactamases/genetics
- beta-Lactamases/metabolism
- beta-Lactamases/therapeutic use
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Affiliation(s)
- Ralph F Alderson
- Genencor International, a Danisco company, 925 Page Mill Road, Palo Alto, California 94304, USA
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25
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Spunt SL, Smith LM, Ruymann FB, Qualman SJ, Donaldson SS, Rodeberg DA, Anderson JR, Crist WM, Link MP. Cyclophosphamide Dose Intensification during Induction Therapy for Intermediate-Risk Pediatric Rhabdomyosarcoma Is Feasible but Does Not Improve Outcome. Clin Cancer Res 2004; 10:6072-9. [PMID: 15447992 DOI: 10.1158/1078-0432.ccr-04-0654] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE More than half of pediatric rhabdomyosarcoma cases have intermediate-risk features and suboptimal outcome (3-year failure-free survival estimates, 55 to 76%). Dose intensification of known active agents may improve outcome. EXPERIMENTAL DESIGN This pilot study evaluated the feasibility of dose intensification of cyclophosphamide in previously untreated patients ages < 21 years with intermediate-risk rhabdomyosarcoma. Induction therapy comprised four 3-week cycles of VAC: vincristine (V) 1.5 mg/m2 on days 0, 7, and 14; actinomycin D (A) 1.35 mg/m2 on day 0; and dose-intensified cyclophosphamide (C) on days 0, 1, and 2. The three cyclophosphamide dose levels tested were as follows: (a) 1.2 g/m2/dose; (b) 1.5 g/m2/dose; and (c) 1.8 g/m2/dose. Continuation therapy comprised nine additional cycles of VAC with 2.2 g/m2/cycle of C. Radiotherapy was administered at week 0 (parameningeal tumors with intracranial extension) or week 12 or 15 (all others). RESULTS Between October 1996 and August 1999, 115 eligible patients were enrolled. Three of 15 patients treated at dose level 2 experienced life-threatening dose-limiting toxicity (typhlitis +/- other severe toxicity). Dose level 1 was the maximum-tolerated dose, and 91 evaluable patients were treated at this level. The 3-year failure-free and overall survival estimates for patients treated at the maximum-tolerated dose were 52% (95% confidence interval, 41-64%) and 67% (95% confidence interval, 56-77%), respectively, at a median follow-up of 3 years. CONCLUSIONS A 64% increase in the standard cyclophosphamide dosage during induction (to 3.6 g/m2/cycle) was tolerated. However, outcomes were similar to those observed at lower dosages, suggesting that alkylator dose intensification does not benefit patients with intermediate-risk rhabdomyosarcoma.
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Affiliation(s)
- Sheri L Spunt
- St. Jude Children's Research Hospital and University of Tennessee College of Medicine, Memphis, Tennessee 38105-2794, USA.
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26
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Abstract
There is considerable variation in the severity of preparative regimen-related toxicity (RRT) in hematopoietic stem-cell transplantation (HSCT). This variation has been recognized to be due, in part, to the wide variation in the pharmacokinetics (PK) of high-dose chemotherapy (HDC). Consequently, therapeutic drug modeling and pharmacokinetic-directed therapy (PKDT) represents an attractive strategy in this setting. Advances in our understanding of drug metabolism, the nature of the active metabolites, and the ability to measure drug concentrations have led to the point where for some agents it is now possible to treat to a given PK end point with a great deal of reliability. In-depth knowledge of the PK and pharmacodynamics (PD) associations of the agents employed in the high-dose setting will make possible more efficient research into preparative regimen dosing intensity and comparisons of different preparative regimens as well as safer HSCT overall. In this review, we discuss PK and PD studies of high-dose cyclosphamide, melphalan, thiotepa, carmustine, cisplatin, carboplatin, paclitaxel, docetaxel, and busulfan.
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Affiliation(s)
- Y Nieto
- BMT Programs at the University of Colorado, USA
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