In vivo and in vitro evaluation of the alkylating agent carmethizole.
Carmethizole, a novel bis-carbamate alkylating agent, was evaluated in vitro for potential mechanisms of interaction with DNA and in vivo for spectrum and degree of antitumor activity. In vitro, the concentration of carmethizole required to produce a 50% reduction in clonogenic cell survival was identical in O6-alkylguanine DNA alkyltransferase-positive and -negative human cell lines. The CHO cell line UV4, hypersensitive to mono- and bifunctional alkylating agents, was 37-fold more sensitive to carmethizole than normal cells. The UV5 cell line, which is not hypersensitive to cross-linkers, was 13-fold more sensitive to carmethizole than normal cells. Alkaline elution studies in L1210 cells exposed to carmethizole showed the presence of DNA-protein and DNA-DNA cross-links but not DNA strand breaks. These data suggested that the interaction of carmethizole with DNA produces monoadducts, DNA-protein, and DNA-DNA interstrand cross-links at several sites. In vivo, carmethizole was not cross-resistant with 1,3-bis(2-chloroethyl)-1-nitrosourea or Cytoxan as determined by testing against P388 leukemias resistant to the latter 2 agents. Carmethizole activity was similar to that of melphalan across the murine solid tumor panel, which consisted of B16 melanoma; colon adenocarcinomas 11a, 26, and 36; and the KHT sarcoma. Carmethizole, Cytoxan, and melphalan were all active and had comparable activity against the HCT-8 and MX-1 human tumor xenografts. The in vivo spectrum of activity and efficacy of carmethizole was similar to that of melphalan.
Elliott
W L
WL
Parke-Davis Pharmaceutical Research Division, Ann Arbor, Michigan 48105.
Fry
D W
DW
Anderson
W K
WK
Nelson
J M
JM
Hook
K E
KE
Hawkins
P A
PA
Leopold
W R
WR
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002330:Carmustine / Q000494:pharmacology; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D007093:Imidazoles / Q000494:pharmacology*; D007939:Leukemia L1210 / Q000188:drug therapy* / Q000235:genetics; D007941:Leukemia P388 / Q000188:drug therapy* / Q000235:genetics; D008558:Melphalan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007093:Imidazoles; C058107:carmethizole; D008558:Melphalan; D002330:Carmustine