Radiation lethality enhancement with 9-aminocamptothecin: Comparison to other topoisomerase I inhibitors

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

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Purpose: Preclinical studies have demonstrated differences in potency, solubility, and tumor specific activity among the camptothecin (CPT) analogues. 9-Aminocamptothecin (9-AC) has demonstrated greater potency in animal studies than other clinically available Topoisomerase I (Topo I) inhibitors. We sought to determine: (a) if 9-AC enhanced the lethal effects of ionizing radiation to a greater extent than other Topo I inhibitors; and (b) the biological and biochemical characteristics of the enhancement. Methods and Materials: Quiescent radioresistant human melanoma (U1-Mel) cells were x-irradiated (1-7 Gy) and exposed to various concentrations of 9-AC (0.1 -100 μM), either before (for 4 h), during, or after (for 4 h) irradiation. Survival was determined via colony forming assays and normalized to correct for drug cytotoxicity. The effects of 9-AC on radiation-related potential lethal damage repair (PLDR) was also measured. A modification of the SDS-KCl assay was used to quantify DNA-Topo I complexes. Results: Enhancement of radiation lethality was observed using confluent U1-Mel cells. The sensitizer enhancement ratio (SER) after a 4 h postirradiation exposure of 10 μM 9-AC was 2.5 at 10% survival. Toxicity from the drug alone was greater than topotecan (TPT), but less than CPT. The radiation synergy effect was: (a) dependent on drug concentration (≤ 2 μM); (b) dependent on timing, with enhancement present only when the drug was present at the time of, or shortly after, radiation; and (c) irreversible, with inhibition of PLDR. Exposure to 9-AC during or after irradiation substantially elevated the number of DNA- Topo I complexes (four- to tenfold) over control levels and correlated with enhanced loss of survival. Conclusion: 9-Aminocamptothecin enhanced radiation lethality in vitro at low drug concentrations with characteristics similar to other Topo I inhibitors. A greater SER, but greater lethality with the drug alone, was obtained in comparison to TPT. The clinical implications of these findings remain unexplored.

Original languageEnglish (US)
Pages (from-to)369-376
Number of pages8
JournalInternational Journal of Radiation Oncology Biology Physics
Volume36
Issue number2
DOIs
StatePublished - Sep 1 1996

Keywords

  • 9-Aminocamptothecin
  • DNA repair
  • PLDR
  • Topoisomerase I

ASJC Scopus subject areas

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

Fingerprint Dive into the research topics of 'Radiation lethality enhancement with 9-aminocamptothecin: Comparison to other topoisomerase I inhibitors'. Together they form a unique fingerprint.

  • Cite this