cc-1065 and Melanoma

The synthesis of an achiral seco-hydroxy-aza-CBI-TMI analog (8) of the duocarmycins is reported. Its specificity for the DNA minor groove of AT-rich sequences and covalent bonding to adenine-N3 was ascertained by a thermal cleavage assay. Compound 8 was found to be cytotoxic in the nanomolar range against murine and human cancer cells. It was further demonstrated that compound 8 was active against murine melanoma (B16-F0) grown in C57BL/6 mice. Compound 8 was also shown to inhibit the growth of the protozoan parasites Leishmania donovani, Leishmania mexicana, Trypanosoma brucei, and Plasmodium falciparum in culture.

Topics: Animals; Antibiotics, Antineoplastic; Antiprotozoal Agents; Cell Line, Tumor; DNA; Drug Screening Assays, Antitumor; Duocarmycins; Female; Humans; Indoles; Melanoma; Mice; Mice, Inbred C57BL; Parasitic Sensitivity Tests; Pyrrolidinones

Topics: Animals; Antibiotics, Antineoplastic; Cell Line; Cell Survival; Cricetinae; DNA; Duocarmycins; Female; Humans; Indoles; Leucomycins; Leukemia, Experimental; Macromolecular Substances; Melanoma; Mice; Neoplasm Transplantation; Ovary; Time Factors

CC-1065 (NSC 298223) is the most cytotoxic agent tested against cells in culture in our laboratory. The 50% lethal doses for exponentially growing B16 melanoma and Chinese hamster ovary cells were 0.44 and 0.14 ng/ml, respectively, as compared to 35 and 500 ng/ml for Adriamycin. In the human tumor-cloning assay, 1-hr exposure to CC-1065 (0.1 ng/ml) caused greater than or equal to 50% lethality in a broad spectrum of tumors. The dose-survival curves for B16 and Chinese hamster ovary cells were characterized by an initial shoulder followed by an exponential decline with increasing dose. CC-1065 was more lethal to exponentially growing B16 cells (50% lethal dose = 0.44 ng/ml) than to plateau-phase cells (50% lethal dose = 1.2 ng/ml). CC-1065 inhibited DNA synthesis much more than did RNA or protein synthesis. After a 2-hr incubation with drug, inhibition of DNA synthesis was low immediately (0 hr) after drug exposure and reached maximum inhibition about 20 hr later. The doses for 50% inhibition of growth (0.18 ng/ml), survival (0.44 ng/ml), and DNA synthesis (0.15 ng/ml) were in the same range, whereas RNA synthesis was inhibited 50% at a much higher dose (5 ng/ml).

Topics: Animals; Antibiotics, Antineoplastic; Blood; Cell Division; Cell Line; Cell Survival; Cricetinae; Culture Media; DNA, Neoplasm; Duocarmycins; Female; Humans; Indoles; Kinetics; Leucomycins; Melanoma; Mice; Neoplasm Proteins; Neoplasms; Ovary; RNA, Neoplasm