Wild-type p53 protein potentiates cytotoxicity of therapeutic agents in human colon cancer cells.
Wild-type p53 is induced by DNA damage. In different cell types, this induction is suggested either to facilitate DNA repair by inducing a cell cycle pause or to potentiate cell death via apoptosis. Wild-type p53 in different cell types has similarly been associated with either enhancement of or increased resistance to the cytotoxicity of many cancer therapeutic agents. We have constructed a colorectal cancer cell line bearing, in addition to endogenous mutant p53 alleles, an exogenous wild-type p53 allele that is under the regulatable control of the lac repressor. Induction of wild-type p53 by isopropyl-beta-thiogalactopyranoside in these cells induces a reversible growth arrest but does not induce cell death. However, we find that the induction of wild-type p53 powerfully potentiates the cytotoxicity of both irradiation and 5-fluorouracil, two agents that are used clinically in the treatment of colorectal cancer. We also find that induction of wild-type p53 potentiates the cytotoxicity of topotecan, a member of the camptothecin family of drugs that also has clinical activity against colon cancer. These findings suggest that the common loss of wild-type p53 in many colorectal cancers may play a role in the clinical resistance of these tumors to anticancer agents. Although some cancer cells may not be directly killed by p53 gene therapy, our findings suggest that genetic alteration of some cancers to induce wild-type p53 may increase their sensitivity to cytotoxic gene therapy.
Yang
B
B
Department of Molecular Biology, University Hospitals of Cleveland, Cleveland, Ohio 44106, USA.
Eshleman
J R
JR
Berger
N A
NA
Markowitz
S D
SD
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D007544:Isopropyl Thiogalactoside / Q000494:pharmacology; D013997:Time Factors; D019772:Topotecan / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D007544:Isopropyl Thiogalactoside; D019772:Topotecan; D005472:Fluorouracil