Camptothecin analogues: studies from the Johns Hopkins Oncology Center.
The camptothecin analogues topotecan and irinotecan (CPT-11) are active anticancer drugs. This article reviews the accumulated results of clinical and laboratory studies performed with these agents at The Johns Hopkins Oncology Center. In a phase I clinical and pharmacology trial of topotecan given as a 30-min infusion daily for 5 days every 3 weeks, profound neutropenia precluded dose escalation above 1.5-2.0 mg/m2 per day, the maximum tolerated dose (MTD). The daily x5 schedule has been developed further with dose escalation using granulocyte-colony-stimulating factor support in patients who have kidney or liver dysfunction and given in combination with cisplatin. In addition, a phase I trial of topotecan given as a 5-day continuous intravenous infusion to patients with refractory leukemia has had promising antileukemic responses. A separate series of in vitro studies indicates that a modest degree of resistance to the cytotoxicity of topotecan can be mediated by P-glycoprotein. A phase I and pharmacology study of irinotecan given as a 90-min infusion every 3 weeks has defined an MTD of 240 mg/m2, with dose escalation being limited by several toxicities. These included an acute treatment-related syndrome of flushing, warmth, nausea, vomiting, and diarrhea; a subacute combination of nausea, diarrhea, anorexia, and weight loss; and/or neutropenia. Antitumor activity has been observed with topotecan and irinotecan in patients with a variety of solid tumors and refractory leukemia in our studies, which supports the widespread enthusiasm for this group of compounds.
Slichenmyer
W J
WJ
Johns Hopkins Oncology Center, Baltimore, MD 21287.
Rowinsky
E K
EK
Grochow
L B
LB
Kaufmann
S H
SH
Donehower
R C
RC
D000970:Antineoplastic Agents / Q000633:toxicity*; D000972:Antineoplastic Agents, Phytogenic / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D002945:Cisplatin / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D007668:Kidney / Q000187:drug effects; D007938:Leukemia / Q000188:drug therapy*; D008099:Liver / Q000187:drug effects; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy*; D010976:Platelet Count / Q000187:drug effects; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D059004:Topoisomerase I Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D019772:Topotecan; D002945:Cisplatin; D002166:Camptothecin