Increased therapeutic benefit through the addition of misonidazole to a nitrosourea-radiation combination.
The potential therapeutic advantage of including the radiosensitizer misonidazole (MISO) in a treatment regimen combining systemic chemotherapy and localized radiotherapy was assessed in the KHT sarcoma. Tumor-bearing C3H mice were treated with 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, administered either alone or in combination with MISO, 24 h prior to irradiating the tumors with doses ranging from 0-35 Gy. The sensitizer exposure was either a single dose of 2.5 mmol/kg or multiple injections given every 0.5 h for 8 h to maintain a sensitizer blood level of approximately 100 micrograms/ml. The chemotherapeutic agent was administered simultaneously with the single sensitizer dose or 3 h into the chronic sensitizer dosing schedule. Tumor responses to the combined modality treatments was determined using end points of tumor regrowth delay and animal tumor-free survival. Skin reactions in the treatment field were scored as a measure of normal tissue complications. MISO, administered as a single dose in the combined modality therapy, enhanced the tumor response by a factor of approximately 1.8-1.9 while increasing skin reactions approximately 1.1- to 1.2-fold. Combining 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea with chronic MISO administration prior to irradiation increased the resultant tumor control probability 1.5- to 1.8-fold without enhancing normal tissue complications. Consequently using MISO as a chemopotentiator in a 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-radiation combination can yield a significant therapeutic benefit.
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D002453:Cell Cycle; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D005260:Female; D008130:Lomustine / Q000008:administration & dosage; D051379:Mice; D008920:Misonidazole / Q000008:administration & dosage; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy / Q000628:therapy*; D012867:Skin / Q000528:radiation effects
D008130:Lomustine; D008920:Misonidazole