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Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells.
Clin Cancer Res. 1997 Sep; 3(9):1653-60.CC

Abstract

Camptothecin (CPT) derivatives are topoisomerase I (top1) inhibitors recently introduced as clinical agents. To explore the role of p53 in CPT-induced cytotoxicity, we examined CPT effects in two isogenic pairs of human cancer cell lines, MCF-7 breast carcinoma and HCT116 colon carcinoma cells, in which p53 function had been disrupted by transfection with the human papillomavirus type-16 E6 gene. Clonogenic survival assays showed that both MCF-7/E6 and HCT116/E6 cells were more sensitive to CPT. No differences in top1 protein levels and activity analyzed by a novel in vitro oligonucleotide assay were observed in the E6 transfectants. Also, CPT showed comparable top1 cleavable complex formation in vivo, as determined by DNA single-strand breaks and DNA protein cross-links. These results suggest that p53 can protect against CPT-induced cytotoxicity and that this protection is mediated downstream of CPT-induced DNA damage. Flow cytometry analyses showed that CPT can induce G1 arrest in cells with normal p53. This G1 arrest was markedly reduced in the p53-deficient cells. These results demonstrate a critical role of p53 as a G1 checkpoint regulator after CPT-induced DNA damage and suggest a rationale for the selectivity of CPT toward tumors with p53 mutations.

Authors+Show Affiliations

Laboratory of Molecular Pharmacology, Division of Basic Sciences, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9815856

Citation

Gupta, M, et al. "Inactivation of P53 Increases the Cytotoxicity of Camptothecin in Human Colon HCT116 and Breast MCF-7 Cancer Cells." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 3, no. 9, 1997, pp. 1653-60.
Gupta M, Fan S, Zhan Q, et al. Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. Clin Cancer Res. 1997;3(9):1653-60.
Gupta, M., Fan, S., Zhan, Q., Kohn, K. W., O'Connor, P. M., & Pommier, Y. (1997). Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 3(9), 1653-60.
Gupta M, et al. Inactivation of P53 Increases the Cytotoxicity of Camptothecin in Human Colon HCT116 and Breast MCF-7 Cancer Cells. Clin Cancer Res. 1997;3(9):1653-60. PubMed PMID: 9815856.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inactivation of p53 increases the cytotoxicity of camptothecin in human colon HCT116 and breast MCF-7 cancer cells. AU - Gupta,M, AU - Fan,S, AU - Zhan,Q, AU - Kohn,K W, AU - O'Connor,P M, AU - Pommier,Y, PY - 1998/11/17/pubmed PY - 1998/11/17/medline PY - 1998/11/17/entrez SP - 1653 EP - 60 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin. Cancer Res. VL - 3 IS - 9 N2 - Camptothecin (CPT) derivatives are topoisomerase I (top1) inhibitors recently introduced as clinical agents. To explore the role of p53 in CPT-induced cytotoxicity, we examined CPT effects in two isogenic pairs of human cancer cell lines, MCF-7 breast carcinoma and HCT116 colon carcinoma cells, in which p53 function had been disrupted by transfection with the human papillomavirus type-16 E6 gene. Clonogenic survival assays showed that both MCF-7/E6 and HCT116/E6 cells were more sensitive to CPT. No differences in top1 protein levels and activity analyzed by a novel in vitro oligonucleotide assay were observed in the E6 transfectants. Also, CPT showed comparable top1 cleavable complex formation in vivo, as determined by DNA single-strand breaks and DNA protein cross-links. These results suggest that p53 can protect against CPT-induced cytotoxicity and that this protection is mediated downstream of CPT-induced DNA damage. Flow cytometry analyses showed that CPT can induce G1 arrest in cells with normal p53. This G1 arrest was markedly reduced in the p53-deficient cells. These results demonstrate a critical role of p53 as a G1 checkpoint regulator after CPT-induced DNA damage and suggest a rationale for the selectivity of CPT toward tumors with p53 mutations. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/9815856/Inactivation_of_p53_increases_the_cytotoxicity_of_camptothecin_in_human_colon_HCT116_and_breast_MCF_7_cancer_cells_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9815856 DB - PRIME DP - Unbound Medicine ER -