Topotecan in chronic lymphocytic leukemia.
BACKGROUND
Topotecan is one of a new class of agents that targets topoisomerase I (Topo I) and stabilizes the DNA-topo1 complex, ultimately resulting in cell death. The rationale for the use of topotecan in chronic lymphocytic leukemia (CLL) is based on the finding that levels of Topo I are elevated in the lymphocytes of patients with this disease.


METHODS
Twelve patients with CLL were treated with topotecan to assess its clinical efficacy; in addition, DNA-protein cross-linking was measured after exposure of the cells to topotecan, in an attempt to correlate potential anti-CLL effects with this parameter. The median age of the patients was 63 years; all had received prior therapy with fludarabine and four (33%) were resistant to fludarabine. Four patients (33%) had also received therapy with chlorambucil, and three of them were resistant to this agent. Seven patients (58%) were Rai stage I-II and five (42%) were Rai stage III-IV. Topotecan was given as a 30-minute infusion at a daily dose of 2 mg/m2 for 5 days, and courses were repeated monthly. Cells were obtained from the patients before treatment and exposed to 2 microM topotecan or control in vitro. In addition, cells were obtained from patients after they received the first dose of topotecan and protein-bound DNA was measured with the same technique.


RESULTS
No patient responded to therapy with topotecan (95% confidence interval, 0-27%). Nonhematologic toxicity was mild and thrombocytopenia occurred in four of eight patients whose conditions could be evaluated. One patients died of myocardial infarction and another died of fungal pneumonia. DNA-protein cross-linking was detected in all nine patients whose cells were assessed in vitro, with levels of cleavable complex ranging from twofold to 7.5-fold that of the control cells. Only two of eight patients with evaluable conditions had increased cross-linking detectable in circulating cells after the first dose of topotecan, which was consistent with the drug's lack of effect in vivo.


CONCLUSIONS
Although exposure of cells from patients with CLL to topotecan in vitro at 2 microM resulted in detectable protein-DNA cross-linking, this effect was not seen in patients who received a bolus dose of 2 mg/m2, and no remissions were noted in 12 patients.
O'Brien
S
S
Department of Hematology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Kantarjian
H
H
Ellis
A
A
Zwelling
L
L
Estey
E
E
Keating
M
M
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D003432:Cross-Linking Reagents; D004264:DNA Topoisomerases, Type I / Q000187:drug effects; D004273:DNA, Neoplasm / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D019772:Topotecan; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin