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⊙临床研究 CLINICAL RESEARCH⊙
自体干细胞结合高剂量动脉化疗晚期胃癌作用研究
朱金水,朱
励,王 龙,庄奇新,胡
兵,达 炜,陈维雄,陈国强,马积庆
朱金水,朱励,王龙,
庄奇新,胡兵,达炜,陈维雄,上海交通大学附属第六人民医院消化科
上海市200233
陈国强,国家南方基因中心血液分子研究室
上海市 200025
马积庆,复旦大学附属肿瘤医院
上海市 200031
朱金水，男，1965-07-05生，安徽省安庆市人，主任医师，教授，1995年获上海第二医科大学博士学位，上海第二医科大学研究生导师，发表论文110篇，目前任中华医学会肿瘤免疫专业副主任委员及中国中西医结合学会上海消化专业副主任委员.
上海市第六人民医院重点项目，六院科字，No.
ZDI 2000-4
项目负责人 朱金水,200233,上海市,上海交通大学附属第六人民医院.
zhujs1803@hotmail.com
电话:021-54778507
收稿日期 2002-05-18
接受日期 2002-07-20
Autologous peripheral blood stem cell
combined with high-dose arterial chemotherapy for advanced gastric cancer
Jin-Shui Zhu, Li Zhu, Long Wang, Qi-Xin Zhuang,Bin Hu,Wei Da, Wei-Xiong
Chen, Guo -Qiang Chen,Ji-Qing Ma
Jin-Shui Zhu, Li Zhu, Long Wang, Qi-Xin
Zhuang,Bin Hu,Wei Da, Wei-Xiong Chen , Department of Gaseroenterology, Sixth
People抯 Hospital,
Shanghai Jiaotong University, Shanghai 200233, China
Guo -Qiang Chen, China South Gene Center, Shanghai 200025, China
Ji-Qing Ma, Cancer Hospital, Fudan University, Shanghai 200030, China
Supported by The Primary Science and Technology Project of Shanghai Sixth
People抯 Hospital,
No.ZDI2000-4
Correspondence to:Professor Jin-Shui Zhu, Department of Gaseroenterology,
Sixth People抯 Hospital,
Shanghai Jiaotong University, Shanghai 200233, China. zhujs1803@hotmail.com
Received 2002-05-18 Accepted 2002-07-20
Abstract
AIM:To evaluate immune modulator of high dose EAP (etopside + etopmycine +
carplatine) arterial chemotherapy combined with autologous peripheral blood stem
cell transplantation (APBSCT) in the treatment of patients with late gastric
cancer.
METHODS:All patients accepted arterial chemotherapy or/and combined with
autologous peripheral blood stem cell transplantation.
RESULTS:Effective rate of EAP arterial chemotherapy combined with APBSCT was up
to 85. 0 % (17/20), compared with control group (35.0 %, 7/20) in late stage of
gastric cancer. APBSCT enhanced obviously the proliferation of peripheral blood
cells and expression of serum interleukin-2 receptor and interferon-gamma levels
in the patients. Mean volumes of gastric cancer were 40.5±3.4
cm3 and 39.4±3.2
cm3 respectively before chemotherapy, and 16.7±1.4
cm3 and 30.2±2.6
cm3 after treatment using different regiment 4 weeks. The difference
between the groups was significant. Interleukin-2, interferon-gamma, serum
interleukin-2 receptor were 21.72 ±2.3
ku.L-1, 632.9±47.8
ku.L-1,768.3±67.2
ku.L-1
and 79.3±7.4
ku.L-1,2356.5±121.3
ku.L-1,and 234.8 ±12.9
ku.L-1 respectively before chemotherapy. After 4 weeks EAP arterial chemotherapy
combined with APBSCT, the two groups were significantly different (P <0.01).
CONCLUSION:EAP arterial chemotherapy
combined with APBSCT was a new effective scheme for the treatment of late
gastric cancer with malignant ascites; APBSCT may restore patient's immune
and hematopoietic reconstruction,and it can decrease side-effects of high-dosage
arterial chemotherapy,and improved the patient's immune
modulator function.
Zhu JS, Zhu L, Wang L, Zhuang QX, Hu B, Da W, Chen WX , Chen GQ, Ma
JQ.Autologous peripheral blood stem cell combined with high-dose arterial
chemotherapy for advanced gastric cancer. Shijie huaren xiaohua zazhi
2002;10(12):1408-1411
摘要
目的:本文采用自体外周造血干细胞联合高剂量超选择胃左动脉化疗晚期胃癌患者，探讨其近期疗效及对机体免疫调节因子影响.
方法:所有晚期胃癌患者采用数字化血管造影（DSA）引导下超选择高剂量动脉EAP方案化疗后，均接受自体外周血干细胞移植.
结果:自体外周血干细胞移植结合高剂量EAP动脉化疗治疗组对晚期胃癌有效率为85.0
%,治疗前肿瘤体积为40.5±3.4
cm3 ,1疗程后16.7±1.4
cm3；而全身静脉EAP化
疗晚期胃癌有效率为35.0 %,治疗前肿瘤体积为39.4±3.2
cm3 , 1疗程后30.2±2.6
cm3 ；动脉化疗后再输注自体外周造血干细胞胃癌患者，其机体白介素-2
,g-干扰素，可溶性白介素-2受体则显著下降.
结论:自体外周造血干细胞联合高剂量EAP动脉化疗方案是治疗不能手术晚期胃癌新方法，同时还可提高机体中央免疫调节因子IL-2,g-干扰素水平，降低免疫抑制因子sIL-2R功能.
朱金水,朱励,王龙,庄奇新,胡兵,达炜,陈维雄,陈国强,马积庆.自体干细胞结合高剂量动脉化疗晚期胃癌作用研究.世界华人消化杂志
2002;10(12):1408-1411
0 引言
胃癌是我国最常见的恶性肿瘤之一，在消化道肿瘤中占首位，居我国恶性肿瘤第2位[1-25]
.手术切除是治疗胃癌的首选方案，但有四分之三患者就诊时属于中晚期，已失去手术时机，还有不少患者因合并其他疾病不宜手术，常规静脉化疗疗效不佳，全身化疗毒副作用大，患者耐受性差，延长其生存期及改善生活质量并不令人满意[26-45]
.选择不宜手术的中晚期胃癌患者，行DSA超选择性胃癌供血动脉局部插管化疗，灌注高剂量肿瘤敏感的化疗药，并辅自体外周造血干细胞移植（APBSCT）使患者能耐受高剂量化疗药物的副反应，国内尚未报道.
1 材料和方法
1.1材料 Ⅲ-Ⅳ胃癌(TNM分型)
40(男22，女18)例，年龄25-70岁，均为不能手术或不愿住院患者，均经胃镜及病理活检证实为胃窦低分化腺癌，其中15例有癌性腹水，5例患者因合并高血压及糖尿病拒绝手术，治疗前后未使用干扰素、胸腺肽等免疫制剂，并随机分成PBSCT结合动脉插管化疗治疗组和全身静脉化疗对照组，并采用超声胃镜测定两组患者治疗前及1疗程后肿瘤体积变化值.
1.2方法
治疗组：局部超选择胃左动脉插管化疗前采用GSF剂量每天6
ug/Kg，连续皮下注射5-7 d,采用CS3000型仪自
动分离患者外周血干细胞,达到2×1011/L,然后储存到-70 ℃液氮罐中，两次高剂量EAP动脉化疗，每次EAP动脉化疗后48
h开始回输自体外周血干细胞，4 wk为1疗程；对照组：Ⅲ-Ⅳ胃癌（TNM分型）20（男10，女10）例，年龄30-68岁，均为不能手术胃癌患者，采用全身静脉化疗EAP方案，每1
wk内第1，3，5天静脉滴注VP16，即足叶乙甙，4
mg/Kg, 第7天阿霉素1.2
mg/Kg,第2，7天静脉滴注卡铂4
mg/Kg; 隔1 wk重复1次，4
wk为1疗程，然后考察其近期疗效，EAP改良插管动脉化疗方案：E
在数字化血管造影仪引导下根据肿瘤供血动脉选择胃左或胃十二指肠动脉灌注化疗，1
wk/次，间隔1 wk后进行第2次化疗，1
wk后通过内镜超声测定胃肿瘤体积大小.动脉化疗前及1疗程后分别采取胃癌患者外周血5
mL,分离血清及淋巴细胞，分别采用Elisa法检测其IL-2,g-IFN,sIL-2R水平
统计学处理 应用SAS软件进行t检验.
2 结果
2.1自体干细胞结合高剂量EAP动脉化疗治疗晚期胃癌患者20例，连续2次高剂量EAP动脉化疗后，再采用自体外周血干细胞移植1
wk后，胃癌患者外周清中IL-2，g-IFN水平升高，sIL-2R水平显著下降(表1)
表1 晚期胃癌自体干细胞结合EAP动脉化疗后IL-2、g-IFN、sIL-2R水平影响(
ku/L,n =20 )
| 分组 | IL-2 | g-IFN | sIL-2R |
| 治疗前 | 21.72±2.3 | 632.9±47.8 | 768.3± 67.2 |
| 治疗后 | 79.3±7.4b | 2356.5±121.3b | 234.8 ±12.9b |
bP <0.01, vs 治疗前
2.2自体干细胞结合高剂量EAP动脉化疗治疗晚期胃癌患者20例，连续2次高剂量EAP动脉化疗，全身静脉化疗治疗晚期胃癌患者20例近期有效率为35.0
%，两者比较有显著性差异;P <0.01(表2).
表2 自体干细胞结合EAP动脉化疗与静脉化疗对晚期胃癌近期有效率比较(n=20,
)
| 分组 | CR | PR | 有效率(%) |
| 对照组 | 1 | 6 | 35.0 |
| 治疗组 | 2 | 15 | 85.0b |
bP <0.01, vs 对照组
2.3 治疗组与对照组治疗前超声胃镜测定胃癌肿体积分别为40.5±3.4
cm3,39.4±3.2
cm3;1疗程后分别为16.7±1.4
cm3,30.2±2.6
cm3；统计学比较治疗组肿瘤体积显著缩小(P
<0.01)且显著优于全身静脉EAP化疗对照组治疗晚期胃癌近期疗效；而对照组肿瘤体积有缩小,但不显著(P
<0.05).
3 讨论
近年来，国内外已有多家医院进行了胃癌的介入化疗，研究显示术前高选择性动脉插管化疗治疗胃癌由于药物直接进入肿瘤血管，局部浓度高，且可避免全身静脉化疗时药物与血浆蛋白结合失去抗癌活性，故可明显提高抗癌效果，毒副反应轻，能提高手术切除率和根治率，且对减少或防止术中瘤细胞医源性扩散、种植及术后复发有重要的临床意义[2,3]
.有研究显示胃癌血供的主要动脉是胃左动脉(83.
3 %),其次为胃十二指肠动脉、胰十二指肠动脉、胃后动脉及左膈下动脉和胃右动脉，而采用DSA（数字血管造影）进行超选择胃癌供血动脉插管化疗国内鲜有报道.从胃癌的供血动脉进行超选择性、超剂量的动脉插管化疗，有效率高，疗效好，相比全身静脉化疗毒副作用少；作者等研究表明自体外周血干细胞移植支持下局部插管化疗近期疗效显著高于全身静脉化疗，但同时局部插管化疗和静脉化疗一样也有胃肠道毒性和骨髓抑制等副反应，亦有剂量限制，而多数抗癌化疗药的细胞杀伤作用呈浓度依赖性，采用自体外周血干细胞移植支持下局部插管化疗则可避免全身化疗毒副反应，又可避免化疗后引起白细胞下降所致感染，目前国内外检索尚无该方法治疗中晚期胃癌的报道[56-62].故寻找合理有效的方法提高中晚期胃癌患者超选择胃癌供血动脉插管化疗对高剂量化疗的耐受性是提高中晚期胃癌疗效的关键.
1990年以来,自体骨髓移植(autologus
bone marrow transplantation, ABMT)和自体外周血干细胞移植（APBSCT）逐渐应用于恶性肿瘤的治疗，通过造血重建和免疫重建使患者可以接受超大剂量的化疗和放疗，从而提高临床疗效[10-19].
90年代中后期，采用静脉高剂量EAP方案化疗治疗胃癌，并用自体骨髓解救，近期疗效好[20-35]
.因自体外周血干细胞移植APBSCT
与自体骨髓移植相比，有移植后造血及免疫重建早、并发症少、采集方便、不需麻醉等优点，已广泛地应用于淋巴瘤、骨髓瘤、白血病等，取得了较好的临床效果，有取代ABMT之趋势.在实体瘤方面，APBSCT已应用于乳腺癌、肺癌及卵巢肿瘤等，显示其可有效地防止大剂量化疗时骨髓的抑制作用，使缓解率提高，使无瘤生存期延长[36-62].但目前在国内外尚无APBSCT支持下超选择高剂量胃癌供血动脉插管化疗治疗中晚期胃癌的文献报道，本文采用自体造血干细胞结合超选择高剂量动脉化疗治疗了20例不能手术晚期胃癌患者,近期有效率85.0
%显著高于EAP方案全身静脉化疗35.0
%近期有效率，
且前者显著提高了患者免疫调节因子白介素-2及干扰素水平，降低了免疫抑制因子可溶性白介素-2受体产生，说明自体造血干细胞支持有利于胃癌患者化疗后机体免疫功能恢复，从而提高高剂量
EAP动脉化疗方案顺利进行创造了条件，因此值得临床上进一步推广.
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