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In Vivo Potentiation of 1-(2-Chloroethyl)-3-cyclohexyl-1-nitrosourea by the Radiation Sensitizer Benznidazole¹

Experimental Therapeutics Division [D. W. S., S. M., K. W.] and Department of Radiation Biology and Biophysics [D. W. S.], University of Rochester Cancer Center, Rochester, New York 14642

Recent studies in mouse tumor systems have indicated a potential therapeutic advantage in combining the radiosensitizer misonidazole (MISO) with cancer chemotherapy drugs. One agent the antitumor activity of which has been enhanced to a greater extent than its hematological or gastrointestinal toxicities is the nitrosourea, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU). Recently, sensitizers more lipophylic than MISO have been reported to give greater tumor response enhancement when combined with CCNU. The present studies compared the potential therapeutic benefit of combining MISO (partition coefficient, 0.43) or benznidazole (BENZO) (partition coefficient, 8.5) in KHT sarcoma or RIF-1 tumor-bearing C3H mice. Both sensitizers were administered i.p. and given either 30 min before (BENZO) or simultaneously with (MISO) the chemotherapeutic agent. Survival of clonogenic tumor cells assessed 22 to 24 hr after treatment or in situ tumor growth delay were used as assays of tumor response. Normal tissue toxicity was determined using the drug dose yielding 50% animal lethality in 30 days end point. When combined with CCNU, doses of MISO (5.0 mmol/kg) or BENZO (0.3 mmol/kg) were found to yield approximately equivalent increases in both the tumor effect (enhancement ratio, 1.8 to 2.0) and normal tissue toxicity (enhancement ratio 1.3 to 1.4). Both sensitizers therefore led to a therapeutic benefit. However, although a 10-fold lower dose of the more lipophylic sensitizer BENZO proved to be as effective as MISO at enhancing the tumoricidal effects of CCNU, this dose reduction did not result in a greater therapeutic gain for BENZO.

¹ This work was presented in part at the 73rd Annual Meeting of the American Association for Cancer Research, St. Louis, Mo., April 1982 (20). The support of NIH Grants CA-11051, CA-20329, and CA-11198 is gratefully acknowledged.

² To whom requests for reprints should be addressed, at Experimental Therapeutics Division, University of Rochester Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, N. Y. 14642.

Received 8/30/82. Accepted 12/ 1/82.