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Objective. CZ48, a lactone-stablized camptothecin-C20-propionate, exerts S-phase specific cytotoxicity after its hydrolysis to camptothecin. Manumycin A (MA), a farnesyltransferase inhibitor, induces cell rest at G1 phase. This study was to test the hypothesis that the cytotoxic activity of CZ48 in lung cancer cell lines could be enhanced by MA through the combination of the distinct cell cycle-specific activities of the two agents. Methods. CZ48 was evaluated at 0.103-25 μM alone, or in combination with MA at 0.25-25 μM for cytotoxicity in five human non-small cell lung cancer cell (NSCLC) lines, H1734 (adenocarcinoma, p53 wild type), H522 (adenocarcinoma, p53 mutated), H460 (pleural effusion, p53 wild type), H358 (bronchioalveolar carcinoma, p53 null) and H2444 (epithelial NSCLC from non-smoker). Cells of 2x104/100 μl medium were inoculated in 96-well plates and incubated at 37oC for 24 hr. CZ48 with or without MA were added and incubated with the cells for 48 hr. The cell survival in each well was monitored by XTT assay. The cell line sensitivity to cytotoxicity of CZ48 was established by IC50 for each cell line. The enhancing effect of MA on the cytotoxicity of CZ48 was characterized for individual cell lines. Results. H1734 was most sensitive to CZ48 treatment with IC50 of 0.8 μM, followed by H358 of 15 μM. The remaining three lines, H2444, H522 and H460 were insensitive to CZ48 treatments with IC50 of > 25 μM. The IC50 of MA in these lines were 10, 10.5, 15, 4 and 6 μM, respectively. The cytotoxicity of CZ48 was significantly enhanced by MA. The IC50 values of CZ48 were reduced from 0. 8 to 0.3 μM with 3 μM of MA in H1734; and from 15 to 2.8, 0.9, 0.3 and 0.1 μM with 0.7, 1, 1.7 and 2 μM of MA, respectively, in H358. The IC50 in insensitive lines were substantially reduced from 25 μM to 0.3 μM with 10.5 μM of MA in H2444, 0.9 μM with 3 μM of MA in H522, and 0.3 μM with 3.5 μM of MA in H460. Conclusions. The combination of CZ48 with MA exerts significant enhanced cytotoxic effects on the five NSCLC lines with various etiology and p53 expressions, and warrants further in vivo evaluations.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]