Carmethizole hydrochloride [1-methyl-2-methylthio-4,5-bis(hydroxymethyl)
imidazole-4', 5'-bis(N-methylcarbamate)hydrochloride, NSC 602,668; hereafter called
carmethizole] is a new
antitumor drug that has shown relatively broad activity in initial evaluations against several murine
tumors and human
tumor xenografts in vivo. The present studies were designed to address questions about
carmethizole's activity against established disease, its activity on different treatment schedules, and the extent of its cross-resistance with established drugs. Human MX-1
mammary carcinoma, human NCI-H82
small-cell lung carcinoma, and human LOX
amelanotic melanoma xenografts in athymic mice were used to determine the
drug's activity against established disease; the NCI-H82 lung-
tumor xenograft in athymic mice was used to explore its schedule dependence; and a series of
drug-resistant murine
leukemias provided an in vivo cross-resistance profile. When injected i.p.,
carmethizole exhibited antitumor activity against advanced-stage s.c. MX-1 mammary, s.c. NCI-H82 lung, and i.p. LOX
melanoma xenografts and was as effective against established disease (MX-1 and LOX) as it was against early-stage disease (no data are available for early-stage NCI-H82). The
therapeutic effect of
carmethizole was not route-dependent, as was evidenced by the similar delays observed in
tumor growth following i.p. and i.v. administration. The use of a split-dose schedule on a single day instead of one bolus injection yielded an increase in the total dose delivered, resulting in an increased delay in
tumor growth. Murine
leukemias resistant to
vincristine (VCR),
amsacrine (
AMSA), or
methotrexate (MTX) were not cross-resistant to
carmethizole. However, murine
leukemias resistant to
doxorubicin (ADR),
melphalan (
L-PAM),
cisplatin (DDPt), 1-beta-D-ara-binofuranosylcytosine (
ara-C), and
5-fluorouracil (5-FU) were cross-resistant to
carmethizole, suggesting that patients who have previously been treated with any of these agents might be less likely to respond to
carmethizole than those who have had no opportunity to develop resistance to any of these compounds. We anticipate that the information derived from these studies may be useful in the design of clinical trials of
carmethizole and may stimulate additional basic research on the mechanism of action of this new agent.