Inhibition and recovery of DNA synthesis in host tissues and sensitive and resistant B16 melanoma after 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea, a predictor of therapeutic efficacy.
Single doses of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea caused transient suppression of [3H]thymidine incorporation into DNA in bone marrow and gastrointestinal mucosa and more prolonged inhibition of such incorporation in B16 melanoma. A single dose of 1-(2-chloroethyl) -3- (trans-4-methylcyclohexyl) -1-nitro-sourea, 16 mg/kg, doubled the mean life-span after treatment of C57BL times DBA/2F1 male mice bearing 12-day-old B16 melanomas. Subsequent doses timed to minimize toxicity and maximize antitumor effect, however, produced no further prolongation of survival, and studies with B16 melanoma previously expsed to 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea demonstrated that the suppression of [3H]thymidine incorporation into DNA was no longer prolonged beyond that seen with normal host tissues. The loss of clinical efficacy was accompanied by a loss of differential suppression of [3H]thymidine incorporation into DNA between the tumor and host tissues.
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis*; D004273:DNA, Neoplasm / Q000096:biosynthesis*; D003864:Depression, Chemical; D005753:Gastric Mucosa / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism; D009607:Nitrosourea Compounds / Q000494:pharmacology*; D012673:Semustine / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D013936:Thymidine / Q000378:metabolism
D004273:DNA, Neoplasm; D009607:Nitrosourea Compounds; D012673:Semustine; D004247:DNA; D013936:Thymidine