Investigation of the comparative effects of 2-chlorodeoxyadenosine on tumor colony forming units in vitro.
2-CdA is a deaminase-resistant purine analogue which has shown clinical activity against various hematological tumors, and is currently undergoing clinical phase II trials. The objectives of our study were to determine the activity of 2-CdA against freshly explanted clonogenic cells from non-hematological human tumors and compare this agent with other 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. Inhibition of tumor specimens was concentration-dependent: 0.57 ng/ml: 1/51 (2%), 5.7 ng/ml: 4/52 (7%), 57 ng/ml: 11/52 (21%), 114 ng/ml: 27/50 (54%). At concentrations > or = 57 ng/ml, 2-CdA was as active as cisplatin, doxorubicin, 5-fluorouracil, mitomycin-C, vinblastine, and etoposide. For long-term exposures (21-28 days), final concentration of 2-CdA were 0.57, 5.7, and 57 ng/ml. At 0.57 ng/ml, 2-CdA 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 demonstrated greater activity if the drug exposure time was extended. Using 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 or multiple doses might increase the response rate to about 24%. If higher peak plasma concentration could be achieved, dose-dependent increases in clinical responses might be achievable. We conclude that 2-CdA is active against clonogenic cells from freshly explanted non-hematological human tumor specimens at high concentrations.
Depenbrock
H
H
Technische Universität München, Klinikum rechts der Isar, Germany.
Wenger
M
M
Peter
R
R
Fellbaum
C
C
Block
T
T
Rastetter
J
J
Hanauske
A R
AR
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D017338:Cladribine / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000494:pharmacology*; D005047:Etoposide / Q000008:administration & dosage / Q000494:pharmacology; D005472:Fluorouracil / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage / Q000494:pharmacology; D009369:Neoplasms / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D014410:Tumor Stem Cell Assay; D014747:Vinblastine / Q000008:administration & dosage / Q000494:pharmacology
D000970:Antineoplastic Agents; D015507:Drugs, Investigational; D017338:Cladribine; D016685:Mitomycin; D014747:Vinblastine; D005047:Etoposide; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil