Sequence effect of irinotecan (CPT-11) and topoisomerase II inhibitors in vivo

Cancer Chemother Pharmacol. 1998;42(4):327-35. doi: 10.1007/s002800050825.

Abstract

The DNA topoisomerases I and II are the target of several clinically important antineoplastic agents which produce DNA cleavage by stabilization of the covalent DNA-protein bond with resultant cell death after DNA synthesis is attempted. Depletion of the target topoisomerase and reciprocal changes in the other occur with drug treatment.

Purpose and methods: To develop empiric treatment regimens of combinations and sequences of agents directed against topoisomerase I (irinotecan/CPT-11) and II (etoposide and doxorubicin), in vivo studies were performed in mice bearing the EMT-6 mammary tumor to assess efficacy, host tolerance and the resultant biochemical changes in topoisomerase mRNA and protein.

Results: At 24 h after therapy, depletion of the target topoisomerase mRNA and protein with reciprocal increases in the alternate topoisomerase mRNA and, to a lesser extent, protein were noted. No therapeutic antagonism was found with any combination or sequence of agents, and therapeutic antagonism was noted with concurrent irinotecan/etoposide and sequential doxorubicin/irinotecan. Depletion of target topoisomerases by combined therapy beyond a threshold necessary for therapeutic efficacy produced no additional benefit.

Conclusions: Antineoplastic therapy with combinations of topoisomerase I and II agents is feasible and may produce therapeutic synergy. The appropriate sequence may depend on the particular agents used. The rationale for such therapy, that topoisomerases I and II may have reciprocal and compensatory interactions, is supported by the biochemical data.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives
  • Cell Death / drug effects
  • DNA, Neoplasm / drug effects
  • DNA, Neoplasm / metabolism*
  • Doxorubicin / administration & dosage
  • Drug Interactions
  • Etoposide / administration & dosage
  • Female
  • Irinotecan
  • Mammary Neoplasms, Experimental / drug therapy*
  • Mice
  • Mice, Inbred BALB C
  • RNA, Messenger / metabolism
  • Topoisomerase I Inhibitors*
  • Topoisomerase II Inhibitors*

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents, Phytogenic
  • DNA, Neoplasm
  • RNA, Messenger
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Etoposide
  • Irinotecan
  • Doxorubicin
  • Camptothecin