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  • Session 2: Pharmacology: Preclinical and Phase I Studies of Topoisomerase Dosing Concepts
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Camptothecin analogues: studies from The Johns Hopkins Oncology Center

Abstract

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 ×5 schedule has been developed further with dose escalation using granulocytecolony-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.

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Correspondence to William J. Slichenmyer.

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Slichenmyer, W.J., Rowinsky, E.K., Grochow, L.B. et al. Camptothecin analogues: studies from The Johns Hopkins Oncology Center. Cancer Chemother. Pharmacol. 34, S53–S57 (1994). https://doi.org/10.1007/BF00684864

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Key words

  • Topoisomerase I
  • Camptothecin
  • Cancer chemotherapy