Effect of nucleoside analogue BCH-4556 on prostate cancer growth and metastases in vitro and in vivo.
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.
Department of Medicine, Physiology, and Oncology, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada.
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Rabbani
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Harakidas
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Bowlin
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Attardo
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000556:secondary; D002455:Cell Division / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004148:Dioxolanes / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051381:Rats
D000970:Antineoplastic Agents; D004148:Dioxolanes; C074908:troxacitabine; D004317:Doxorubicin; D003596:Cytosine