In vivo response of KHT sarcomas to combination chemotherapy with radiosensitizers and BCNU.
Female C3H/HeJ mice bearing intramuscularly transplanted KHT sarcomas were treated with a single dose of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU, 30 mg/kg, i.p.) alone or in combination with a single dose of misonidazole (MISO, 1.0 mg/g, i.p.) or its desmethylated metabolite Ro-05-9963 (2.0 mg/g, i.p.). The effectiveness of drug therapy was assessed by a tumour growth-delay assay (i.e. measuring the median time required for tumours to grow to treatment size x 4). The relative efficacy of administering the nitroimidazoles in various schedules ranging from 12 h before to 12 h after BCNU administration also was evaluated. Untreated control KHT tumours grew to the initial size x 4 in a median time of 4 days. No significant growth delay was seen in mice treated with either nitroimidazole alone, whilst treatment with BCNU alone produced a median growth delay of 7 days. Combination chemotherapy with 9963 administration 3 h after BCNU significantly increased the median tumour growth delay to 9 days. However, no significant growth delay was produced in any of the other combinations of these agents. The median growth delay was significantly reduced to 5 days when MISO was administered 3 h before BCNU, whereas MISO administered simultaneously 3,6, or 12 h after BCNU significantly enhanced delays ( 9 days). These results indicate that both MISO and 0063 may be combined with conventional therapeutic agents, in this particular case a nitrosourea, to produce an enhanced tumour response. The production of such a response appears to be nitroimidazole as well as schedule dependent.
D000818:Animals; D002330:Carmustine / Q000008:administration & dosage / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D051379:Mice; D008809:Mice, Inbred C3H; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000627:therapeutic use*; D009593:Nitroimidazoles / Q000627:therapeutic use*; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D013997:Time Factors
D009593:Nitroimidazoles; D008920:Misonidazole; C009997:desmethylmisonidazole; D002330:Carmustine