Gastric cancer is the fifth most common cancer and the third leading cause of cancer death worldwide, posing a severe threat to human health. Surgical resection remains the most preferred option for gastric cancer treatment. However, for advanced gastric cancer, the curative effect of surgical resection is usually limited by the local recurrence, peritoneal carcinomatosis, or distal metastasis. Intraoperative chemotherapy is an attractive in situ adjuvant treatment strategy to reduce the recurrence and metastasis after surgical resection. Here, we designed a 5-fluorouracil (5-FU) and cis-platinum (DDP) co-delivery system based on a biodegradable temperature-sensitive hydrogel (PDLLA-PEG-PDLLA, PLEL) for intraoperative adjuvant combination chemotherapy of gastric cancer. This 5-FU + DDP/PLEL hydrogel system characterized by a special sol-gel phase transition in response to physiological temperature and presented sustained drug release in vitro and in vivo. A strong synergistic cell proliferation inhibition and apoptosis promotion of 5-FU + DDP/PLEL were observed against gastric cancer MKN45-luc cells. After intraperitoneal injection, the dual-drug loaded hydrogel formulation showed superior anti-tumor effects than the single-drug carrying hydrogels and combination of free 5-FU and DDP on the gastric cancer peritoneal carcinomatosis model. The use of hydrogel for dual-drug delivery had benefited to fewer side effects as well. What's more, we established a mouse model for postsurgical residual tumors and peritoneal carcinomatosis of gastric cancer, in which the intraoperative administration of 5-FU + DDP/PLEL also remarkably inhibited the local recurrence of the orthotopic tumors and the growth of the abdominal metastatic tumors, resulting in an extended lifetime. Hence, this developed dual-drug loaded hydrogel system has great potential in the intraoperative chemotherapy of gastric cancer, that suggests a clinically-relevant and valuable option for postsurgical management of gastric cancer.

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Intraoperative chemotherapy could reduce the recurrence and metastasis after surgical resection of gastroenteric tumors.

The collagen gel droplet-embedded drug sensitivity test (CD-DST) was revealed to be useful for predicting the effect of S-1 adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PDAC). However, collection of an adequate number of PDAC cells is difficult due to the surrounding fibroblasts. Thus, the aim of this study was to discover novel biomarkers to predict chemosensitivity based on the CD-DST results. Proteomics analysis was performed using liquid chromatography tandem mass spectrometry (LC–MS/MS). Candidate proteins were validated in patients with 5-FU CD-DST results via immunohistochemistry (IHC). The relationships between the candidate proteins and the effect of the adjuvant S-1 were investigated via IHC. Among the 2696 proteins extracted by LC–MS/MS, C1TC and SAHH could accurately predict the CD-DST results. Recurrence-free survival (RFS) was significantly improved in the IHC-positive group compared with the IHC-negative group in both factors. The negative group did not show a significant difference from the group that did not receive S-1. The double-positive group was associated with significantly prolonged RFS compared to the no adjuvant chemotherapy group. C1TC and SAHH have been shown to be useful biomarkers for predicting 5-FU sensitivity as a substitute for the CD-DST in adjuvant chemotherapy for PDAC.

• adjuvant chemotherapy
• collagen gel droplet-embedded culture drug sensitivity test
• colorectal cancer

AIM: To investigate the antineoplastic potency of the novel insulin-like growth factor 1 receptor (IGF-1R) tyrosine kinase inhibitor (TKI) NVP-AEW541 in cell lines and primary cell cultures of human colorectal cancer (CRC).

METHODS: Cells of primary colorectal carcinomas were from 8 patients. Immunostaining and crystal violet staining were used for analysis of growth factor receptor protein expression and detection of cell number changes, respectively. Cytotoxicity was determined by measuring the release of the cytoplasmic enzyme lactate dehydrogenase (LDH). The proportion of apoptotic cells was determined by quantifying the percentage of sub-G1 (hypodiploid) cells. Cell cycle status reflected by the DNA content of the nuclei was detected by flow cytometry.

RESULTS: NVP-AEW541 dose-dependently inhibited the proliferation of colorectal carcinoma cell lines and primary cell cultures by inducing apoptosis and cell cycle arrest. Apoptosis was characterized by caspase-3 activation and nuclear degradation. Cell cycle was arrested at the G1/S checkpoint. The NVP-AEW541-mediated cell cycle-related signaling involved the inactivation of Akt and extracellular signal-regulated kinase (ERK) 1/2, the upregulation of the cyclin-dependent kinase inhibitors p21^Waf1/CIP1 and p27^Kip1, and the downregulation of the cell cycle promoter cyclin D1. Moreover, BAX was upregulated during NVP-AEW541-induced apoptosis, whereas Bcl-2 was downregulated. Measurement of LDH release showed that the antineoplastic effect of NVP-AEW541 was not due to general cytotoxicity of the compound. However, augmented antineoplastic effects were observed in combination treatments of NVP-AEW541 with either 5-FU, or the EGFR-antibody cetuximab, or the HMG-CoA-reductase inhibitor fluvastatin.

CONCLUSION: IGF-1R-TK inhibition is a promising novel approach for either mono- or combination treatment strategies of colorectal carcinoma and even for CRC chemoprevention.

• Insulin-like growth factor receptor
• Tyrosine kinase
• Colorectal cancer
• Apoptosis
• Cell cycle arrest

• Adenocarcinoma/drug therapy
• Adenocarcinoma/metabolism
• Adenocarcinoma/pathology
• Adenocarcinoma/prevention & control
• Antibodies, Monoclonal/therapeutic use
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Apoptosis/drug effects
• Cell Cycle/drug effects
• Cell Line, Tumor
• Cetuximab
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/metabolism
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/prevention & control
• Cytotoxins/therapeutic use
• Dose-Response Relationship, Drug
• Fatty Acids, Monounsaturated/therapeutic use
• Fluvastatin
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Indoles/therapeutic use
• L-Lactate Dehydrogenase/genetics
• L-Lactate Dehydrogenase/metabolism
• Pyrimidines/pharmacology
• Pyrimidines/therapeutic use
• Pyrroles/pharmacology
• Pyrroles/therapeutic use
• Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
• Receptor Protein-Tyrosine Kinases/drug effects
• Receptor Protein-Tyrosine Kinases/genetics
• Receptor Protein-Tyrosine Kinases/metabolism
• Receptor, IGF Type 1/antagonists & inhibitors
• Receptor, IGF Type 1/drug effects
• Receptor, IGF Type 1/genetics
• Receptor, IGF Type 1/metabolism

Unresectable biliary tract carcinoma is known to demonstrate a poor prognosis. We conducted a single arm phase II study of LFP therapy (5-FU (5-fluorourasil) continuous infusion (CVI) and Low-dose consecutive (Cisplatin) CDDP) for advanced biliary tract malignancies basically on an outpatient basis.

Between February 1996 and September 2003, 42 patients were enrolled in this trial.

By using a total implanted CV-catheter system, 5-FU (160 mg/m²/day) was continuously infused over 24 hours for 7 consecutive days and CDDP (6 mg/m²/day) was infused for 30 minutes twice a week as one cycle. The administration schedule consisted of 4 cycles as one course. RESIST criteria (Response evaluation criteria for solid tumors) and NCI-CTC (National Cancer Institute-Common Toxicity Criteria) (ver.3.0) were used for evaluation of this therapy. The median survival time (MST) and median time to treatment failure (TTF) were calculated by the Kaplan-Meier method.

Patients characteristics were: mean age 66.5(47–79): male 24 (54%): BDca (bile duct carcinoma) 27 GBca (Gallbladder carcinoma) 15: locally advanced 26, postoperative recurrence 16. The most common toxicity was anemia (26.2%). Neither any treatment related death nor grade 4 toxicity occurred. The median number of courses of LFP Therapy which patients could receive was two (1–14). All the patients are evaluable for effects with an over all response rates of 42.9% (95% confidence interval C.I.: 27.7–59.0) (0 CR, 18 PR, 13 NC, 11 PD). There was no significant difference regarding the anti tumor effects against both malignant neoplasms. Figure 2 Shows the BDca a longer MST and TTF than did GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.

The estimated MST and median TTF were 225 and 107 days, respectively. The BDca had a longer MST and TTF than GBca (234 vs 150, 117 vs 85, respectively), but neither difference was statistically significant.

LFP therapy appears to be useful modality for the clinical management of advanced biliary tract malignancy.

• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bile Duct Neoplasms/drug therapy
• Carcinoma/drug therapy
• Cisplatin/administration & dosage
• Dose-Response Relationship, Drug
• Female
• Fluorouracil/administration & dosage
• Gallbladder Neoplasms/drug therapy
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Survival Analysis
• Treatment Outcome

• Adenocarcinoma/pathology
• Apoptosis
• Carcinoma, Squamous Cell/pathology
• Cell Cycle/drug effects
• Cell Proliferation/drug effects
• ErbB Receptors/drug effects
• ErbB Receptors/physiology
• Erlotinib Hydrochloride
• Esophageal Neoplasms/pathology
• Humans
• Protein Kinase Inhibitors/pharmacology
• Protein-Tyrosine Kinases/metabolism
• Quinazolines/pharmacology
• Signal Transduction
• Tumor Cells, Cultured