INVESTIGATION OF THE COMPARATIVE EFFECTS OF 2-CHLORODEOXYADENOSINE ONTUMOR COLONY-FORMING-UNITS IN-VITRO

2-CdA is a deaminase-resistant purine analogue which has shown clinica l activity against various hematological tumors, and is currently unde rgoing clinical phase II trials. The objectives of our study were to d etermine the activity of 2-CdA against freshly explanted clonogenic ce lls from non-hematological human tumors and compare this agent with ot her clinically useful anticancer agents. We also compared short-term ( 1 hour) and long-term (21-28 days) exposures. For short-term exposure (1-hour), final concentrations were 0.57, 5.7, 57, and 114 ng/ml. Inhi bition of tumor specimens was concentration-dependent: 0.57 ng/ml: 1/5 1 (2%), 5.7 ng/ml: 4/52 (7%), 57 ng/ml: 11/52 (21%), 114 ng/ml: 27/50 (54%). At concentrations greater than or equal to 57 ng/ml, 2-CdA was as active as cisplatin, doxorubicin, 5-fluorouracil, mitomycin-C, vinb lastine, and etoposide. For long-term exposure (21-28 days), final con centrations of 2-CdA were 0.57, 5.7, and 57 ng/ml. At 0.57 ng/ml, 2-Cd A was active in 4/54 (7%) specimens [5.7 ng/ml: 13/54 (24%), 57 ng/ml: 40/54 (74%)]. A head-to-head comparison with short-term exposures dem onstrated greater activity if the drug exposure time was extended. Usi ng the strategy for testing other standard agents (in vitro dose of 1/ 10th achievable peak plasma concentration), one would predict clinical response rates for single agent bolus or short-term administration of 2-CdA to be in the neighborhood of 7%. Longer durations of infusion o r multiple doses might increase the response rate to about 24%. If hig her peak plasma concentrations could be achieved, dose-dependent incre ases in clinical responses might be achievable. We conclude that 2-CdA is active against clonogenic cells from freshly explanted non-hematol ogical human tumor specimens at high concentrations.