Rabbani S A, Harakidas P, Bowlin T, Attardo G
Department of Medicine, Physiology, and Oncology, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada.
Cancer Res. 1998 Aug 1;58(15):3461-5.
Prostate carcinoma is a common malignancy among males that results in high morbidity and mortality. Here, we have evaluated the capacity of nucleoside analogue BCH-4556 [beta-L-(-)-dioxolane-cytidine] to control prostate cancer progression in our syngeneic model of rat prostate cancer using the rat prostate cancer cell line Dunning R3227 Mat Ly Lu. Different concentrations (50 microM-1 mM) of BCH-4556 resulted in a marked decrease and, eventually, a complete arrest of Mat Ly Lu cell growth in vitro. Cells were inoculated via intracardiac (i.c.) route into the left ventricle or by s.c. injection into the right flank of male Copenhagen rats. Following i.c. inoculation, experimental animals were treated with 75 mg/kg BCH-4556 twice a day or with vehicle alone for 6 consecutive days, starting from day 1 or day 3 post-tumor cell inoculation. Control and experimental animals were monitored for the development of tumor metastases. Treatment with BCH-4556 did not significantly change the development of skeletal metastases and, hence, the time of development of hind limb paralysis. Experimental animals, however, did show a marked reduction in the incidence and size of tumor metastases at the adrenal glands. Following the development of palpable tumors after s.c. injection of Mat Ly Lu cells on day 8 post tumor cell inoculation, animals were treated i.p. with 25-75 mg/kg BCH-4556 twice a day or with vehicle alone for 6 consecutive days. Control animals developed large primary tumors and macroscopic metastasis to lungs, lymph nodes, kidneys, and spleen. In contrast, experimental animals receiving BCH-4556 showed a marked decrease in tumor volume and metastases after the last injection of BCH-4556. The maximum dose of BCH-4556 (75 mg/kg twice a day) caused a complete arrest in tumor growth that was maintained for up to 4-6 days without any evidence of cytotoxicity. These antitumor effects of BCH-4556 were more marked than those of doxorubicin in blocking tumor growth in this model of prostate cancer, and it continued to be effective following three cycles of treatment, without manifesting any signs of drug resistance.
前列腺癌是男性中一种常见的恶性肿瘤，会导致高发病率和死亡率。在此，我们使用大鼠前列腺癌细胞系Dunning R3227 Mat Ly Lu，在我们的大鼠前列腺癌同基因模型中评估了核苷类似物BCH - 4556 [β - L - (-)-二氧戊环胞苷]控制前列腺癌进展的能力。不同浓度（50微摩尔/升 - 1毫摩尔/升）的BCH - 4556导致Mat Ly Lu细胞在体外生长显著减少，并最终完全停滞。细胞通过心内（i.c.）途径接种到雄性哥本哈根大鼠的左心室，或通过皮下（s.c.）注射接种到右腹侧。心内接种后，从肿瘤细胞接种后的第1天或第3天开始，实验动物每天两次接受75毫克/千克BCH - 4556治疗或仅接受赋形剂治疗，连续6天。对对照和实验动物进行肿瘤转移发展的监测。用BCH - 4556治疗并未显著改变骨转移的发展，因此也未改变后肢麻痹出现的时间。然而，实验动物肾上腺处肿瘤转移的发生率和大小确实显著降低。在肿瘤细胞接种后第8天皮下注射Mat Ly Lu细胞出现可触及肿瘤后，动物每天两次腹腔注射25 - 75毫克/千克BCH - 4556或仅接受赋形剂治疗，连续6天。对照动物形成了大的原发性肿瘤，并出现了肺部、淋巴结、肾脏和脾脏的宏观转移。相比之下，接受BCH - 4556的实验动物在最后一次注射BCH - 4556后，肿瘤体积和转移显著减少。BCH - 4556的最大剂量（每天两次75毫克/千克）导致肿瘤生长完全停滞，这种停滞状态持续长达4 - 6天，且没有任何细胞毒性迹象。在这个前列腺癌模型中，BCH - 4556的这些抗肿瘤作用比阿霉素在阻断肿瘤生长方面更为显著，并且在三个治疗周期后仍继续有效，没有表现出任何耐药迹象。
