Watson S A, Michael D, Justin T A, Grimes S, Morris T M, Robinson G, Clarke P A, Hardcastle J D
Department of Surgery, University Hospital, University of Nottingham, UK.
Int J Cancer. 1998 Mar 16;75(6):873-7. doi: 10.1002/(sici)1097-0215(19980316)75:6<873::aid-ijc9>3.0.co;2-s.
Mature and post-translational precursor gastrin forms are growth factors for colorectal tumours. The immunogen Gastrimmune is composed of the amino terminus of gastrin-17 linked to diphtheria toxoid and raises antibodies in situ which neutralise amidated and glycine-extended gastrin-17. The aim of the study was to determine the effect of treatment with 5-fluorouracil(5-FU)/leucovorin on the antibody titres induced by Gastrimmune and the effect of combination therapy on the growth of the rat colon tumour DHDK12. Gastrimmune was administered to rats s.c. at 3 weekly intervals. The rat colon tumour line DHDK12 was injected into the abdominal wall of BDIX rats. Combinations of 5-FU/leucovorin were injected i.v. on days 1, 3 and 5, with the cycle repeated every 4 weeks. Antibody titres were measured by an ELISA technique. Antibody titres were followed for 40 weeks after Gastrimmune (500 microg.ml(-1)) immunization, with titres peaking between 10 and 20 weeks after a single immunisation and falling by week 30. At termination, no effect was observed on either the histological appearance of the gastro-intestinal tract or the proliferation of the colonic mucosa. Pre- and post-treatment with 5-FU/leucovorin (30 mg.kg(-1)) had no effect on the kinetics and level of antibody response to Gastrimmune. Gastrimmune (200 microg.ml(-1)) and 5-FU/leucovorin combinations (12.5 and 20 mg.kg(-1)) increased the therapeutic effects on the in vivo growth of DHDK12 tumors when compared to the agents given singly. Gastrimmune immunisation may be a therapeutic option for the treatment of colorectal cancer in combination with 5-FU/leucovorin.
成熟的和翻译后加工的前体胃泌素形式是结肠直肠肿瘤的生长因子。免疫原Gastrimmune由与白喉类毒素相连的胃泌素-17的氨基末端组成，能原位产生中和酰胺化和甘氨酸延伸型胃泌素-17的抗体。本研究的目的是确定5-氟尿嘧啶（5-FU）/亚叶酸钙治疗对Gastrimmune诱导的抗体滴度的影响，以及联合治疗对大鼠结肠肿瘤DHDK12生长的影响。每隔3周给大鼠皮下注射Gastrimmune。将大鼠结肠肿瘤细胞系DHDK12注射到BDIX大鼠的腹壁。在第1、3和5天静脉注射5-FU/亚叶酸钙的组合，每4周重复一个周期。通过酶联免疫吸附测定（ELISA）技术测量抗体滴度。在以500μg·ml⁻¹的Gastrimmune免疫后，对抗体滴度进行40周的跟踪，单次免疫后抗体滴度在10至20周达到峰值，到第30周时下降。在实验结束时，未观察到对胃肠道组织学外观或结肠黏膜增殖有任何影响。5-FU/亚叶酸钙（30mg·kg⁻¹）治疗前后对Gastrimmune抗体反应的动力学和水平没有影响。与单独给药相比，Gastrimmune（200μg·ml⁻¹）和5-FU/亚叶酸钙组合（12.5和20mg·kg⁻¹）增强了对DHDK12肿瘤体内生长的治疗效果。Gastrimmune免疫联合5-FU/亚叶酸钙可能是治疗结肠直肠癌的一种治疗选择。
