Journal article
Characterisation of a synergistic interaction between a thymidylate synthase inhibitor, ZD1694, and a novel lipophilic topoisomerase I inhibitor karenitecin, BNP1100: mechanisms and clinical implications
European journal of cancer (1990), Vol.35(6), pp.984-993
1999
DOI: 10.1016/S0959-8049(99)00018-0
PMID: 10533483
Abstract
We developed a combination protocol for inhibitors of thymidylate synthase (TS) and DNA topoisomerase I (Topo I) that can exert highly lethal effects
in vitro against HCT-8 human colorectal cancer cells. The specific schedule was constructed so that a TS inhibitor could induce not only primary DNA damage but also cellular conditions optimal for the efficient action of a Topo I inhibitor. The initial drug treatment consisted of a brief exposure to a quinazoline-based antifolate, ZD1694. After an interval of approximately one cell-doubling time, cells were exposed for 8–24
h to BNP1100, a Karenitecin-class 7-thiomethyl-camptothecin, in the presence of 1–10
μM thymidine; the latter acted as a crucial factor to promote the collision of moving replication forks with the drug-stabilised DNA–Topo I cleavable complexes even under continuous TS inhibition. Clonogenic analyses confirmed that these mechanistically distinct drugs at clinically achievable concentrations worked in a highly synergistic manner, with a maximum effect abolishing the viability of virtually all cancer cells (>99.9%). The pretreatment with ZD1694 increased the amount of DNA-bound Topo I by up to 4-fold and the DNA-damaging capability of BNP1100 by up to 15-fold. The possibility of at least four DNA-damaging pathways is proposed which might have resulted from the individual actions of TS and Topo I inhibitors as well as their concerted actions. Taken together, the present findings provided a logically permissible explanation as to why TS and Topo I inhibitors in concerted interactions induced a highly lethal effect which was more than a simple additive effect. Since these drugs are effective specifically on actively proliferating cancer cells, but not on non-cycling G
0/G
1 cells, this mechanism-based protocol may warrant consideration for clinical verification.
Details
- Title: Subtitle
- Characterisation of a synergistic interaction between a thymidylate synthase inhibitor, ZD1694, and a novel lipophilic topoisomerase I inhibitor karenitecin, BNP1100: mechanisms and clinical implications
- Creators
- S.-i Matsui - Roswell Park Cancer InstituteW Endo - Roswell Park Cancer InstituteC Wrzosek - Roswell Park Cancer InstituteK Haridas - BioNumerikP Seetharamulu - BioNumerikF.H Hausheer - BioNumerikY.M Rustum - Roswell Park Cancer Institute
- Resource Type
- Journal article
- Publication Details
- European journal of cancer (1990), Vol.35(6), pp.984-993
- Publisher
- Elsevier Ltd
- DOI
- 10.1016/S0959-8049(99)00018-0
- PMID
- 10533483
- ISSN
- 0959-8049
- eISSN
- 1879-0852
- Language
- English
- Date published
- 1999
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984359846302771
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