5-chlorodeoxycytidine, a radiosensitizer effective against RIF-1 and Lewis lung carcinoma, is also effective against a DMBA-induced mammary adenocarcinoma and the EMT-6 tumor in BALB/c mice.
5-Chlorodeoxycytidine (CldC), coadministered with modulators of pyrimidine metabolism, is an effective radiosensitizer of murine tumors. Past studies that utilized RIF-1 tumors in C3H mice and Lewis lung carcinoma (LLC) in BDF1 mice have been extended with an emphasis on using multiple cycles of drug administration followed by irradiation of LLC and the use of two additional tumor models. Four of seven cures of BDF1 mice bearing LLC were obtained with three doses of 20 Gy irradiation, in which the first and third dose were preceded by a "Standard Protocol" that includes N-(phosphonacetyl)-L-aspartic acid (PALA), 5-fluorodeoxycytidine (FdC), tetrahydrouridine, and the radiosensitizer, 5-chlorodeoxycytidine. No cures were obtained in groups of mice receiving radiation alone or drugs alone, and there were no "no takes" in untreated control groups (six mice/group). Extensive tumor inhibition, exceeding that obtained with drugs or radiation alone, was obtained with two cycles of drugs and radiation combined when a dimethybenzanthracene-induced mammary adenocarcinoma was used in BALB/c mice. With the EMT-6 tumor in BALB/c mice, doses of 10 and 20 Gy were administered 9 and 16 days after tumor implantation, each preceded with the Standard Protocol; this resulted in a tumor growth delay of 24 days. No tumor growth delay occurred with drugs or radiation alone. The omission of PALA, FdC or CldC from the Standard Protocol resulted in loss of tumor control, which was obtained with the complete protocol. The fact that 5-chlorodeoxycytidine is an effective radiosensitizer in four rodent tumor systems is compelling evidence that it has potential as a radiosensitizer of human tumors, especially in view of its tumor selectivity and its resistance to catabolism when used with modulators of its metabolism, and in view of the high levels of the key enzymes in human tumors, which can convert 5-chlorodeoxycytidine to 5-chlorodeoxyuridine triphosphate, the proximate radiosensitizer.
Greer
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S
Department of Microbiology and Immunology, University of Miami School of Medicine, FL 33136.
Santos
O
O
Gottlieb
C
C
Schwade
J
J
Marion
H S
HS
D015127:9,10-Dimethyl-1,2-benzanthracene; D000230:Adenocarcinoma / Q000139:chemically induced / Q000188:drug therapy / Q000532:radiotherapy; D000818:Animals; D003131:Combined Modality Therapy; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005354:Fibrosarcoma / Q000188:drug therapy / Q000532:radiotherapy; D008175:Lung Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000188:drug therapy / Q000532:radiotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000532:radiotherapy*; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*
D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; C035826:5-chloro-2'-deoxycytidine; D015127:9,10-Dimethyl-1,2-benzanthracene