In vivo potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea by the radiation sensitizer benznidazole
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, approximately 1.8 to 2.0) and normal tissue toxicity (enhancement ratio approximately 1.3 to 1.4). Both sensitizers therefore led to a therapeutic benefit. However, although a approximately 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.
- Research Organization:
- Experimental Therapeutics Division, Department of Radiation Biology and Biophysics, University of Rochester Cancer Center, New York
- OSTI ID:
- 6189536
- Journal Information:
- Cancer Res.; (United States), Vol. 43:3
- Country of Publication:
- United States
- Language:
- English
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63 RADIATION, THERMAL, AND OTHER ENVIRON. POLLUTANT EFFECTS ON LIVING ORGS. AND BIOL. MAT.
MISONIDAZOLE
RADIOSENSITIVITY EFFECTS
NITROSO COMPOUNDS
BIOLOGICAL EFFECTS
TUMOR CELLS
SENSITIVITY
CHEMOTHERAPY
DOSE-RESPONSE RELATIONSHIPS
MICE
RADIATION DOSES
RADIOSENSITIZERS
RADIOTHERAPY
RESPONSE MODIFYING FACTORS
SARCOMAS
SIDE EFFECTS
ANIMAL CELLS
ANIMALS
ANTINEOPLASTIC DRUGS
AZOLES
DISEASES
DOSES
DRUGS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
MAMMALS
MEDICINE
NEOPLASMS
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RADIOLOGY
RODENTS
THERAPY
VERTEBRATES
550603* - Medicine- External Radiation in Therapy- (1980-)
560152 - Radiation Effects on Animals- Animals