Concentration and timing dependence of lethality enhancement between topotecan, a topoisomerase I inhibitor, and ionizing radiation

John P. Lamond, Meizhi Wang, Timothy J. Kinsella, David A. Boothman

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Abstract

Purpose: Topotecan (TPT) is a water-soluble Topoisomerase I (Topo I) inhibitor with reported antineoplastic activity against a variety of solid tumors (including nonsmall cell lung, small cell lung, ovarian, breast, esophageal, and head and neck primaries) and leukemias. We sought to determine: (a) if TPT enhanced the lethal effects of ionizing radiation; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent human radioresistant melanoma (U1-Mel) cells were x-irradiated (1-12 Gy) and exposed to various TPT concentrations (0.1- 300 μM) either before (for 4 h), during, or after (for 4 h) radiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of TPT on radiation-related potential lethal damage repair (PLDR) and sublethal damage repair (SLDR) were measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo 1 complexes. Results: Enhanced radiation lethality by TPT was observed using quiescent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 4 μM TPT was 1.6 at 10% survival. The effect was: (a) dependent on drug concentration, with lethality enhancement and minimal drug lethality alone in the 2-10 μM range for a 4 h posttreatment; (b) dependent on timing, with enhancement observed only when drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR and SLDR. Exposure to TPT during or after radiation substantially elevated DNA-Topo I complexes (four- to tenfold) over control levels and complex formation correlated to some degree with loss of survival. Conclusions: TPT enhanced radiation lethality in vitro at low drug concentrations that are clinically feasible. The rationale and design of an ongoing Phase I that which utilizes concurrent TPT and radiation is discussed.

Original languageEnglish (US)
Pages (from-to)361-368
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume36
Issue number2
DOIs
StatePublished - Sep 1 1996

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Keywords

  • DNA repair
  • DNA-Topo I complexes
  • PLDR
  • SLDR
  • Topoisomerase I

ASJC Scopus subject areas

  • Radiation
  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

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