Pre-clinical evaluation of SN-38 and novel camptothecin analogs against human chronic B-cell lymphocytic leukemia...

The topoisomerase I inhibitor camptothecin and its analogs have potent activity against a wide range of solid tumors and several hematologic malignancies. Previous studies with these compounds using the MTT metabolic inhibition assay have shown significant cytotoxicity against lymphocytes from patients with chronic B-cell lymphocytic leukemia (B-CLL). Yet the water soluble analogue, topotecan, which was inhibitory at > 1 microM in vitro, had no clinical activity in vivo. In the present study, we evaluated the in vitro cytotoxicities of SN-38, the active form of irinotecan, and two newer water soluble camptothecin derivatives 10,11-methylenedioxy-20(S)-camptothecin glycinate (MDCG) and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin glycinate (CMMDCG). These two glycinate esters are prodrugs for 10,11-methylenedioxy-20(S)-camptothecin (MDC) and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC), respectively. Effects on cellular metabolism, induction of apoptosis, and overall cell survival were used to evaluate chemosensitivity. We report that the relative cytotoxic potency for these compounds is MDC > or = CMMDC > or = SN-38 >> TPT > CPT-11, where MDC, CMMDC, and SN-38 were over an order of magnitude more cytotoxic than TPT and CPT-11. We also investigated potential mechanisms underlying the unexpected cytotoxicity of these camptothecin derivatives in B-CLL cells that are known to be arrested in G0/G1 of the cell cycle, and found that this class of compounds inhibited [3H]uridine incorporation. We therefore postulate that the inhibition of RNA rather than DNA synthesis may be responsible for the observed cytotoxicity in non-cycling B-CLL cells.