AffiliationCancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, U.K.
MetadataShow full item record
AbstractThe major disseminated cancers remain stubbornly resistant to systemic therapy. Drug-resistant tumours include both slow and fast growing types, with the carcinomas constituting the major problem. Strategies for drug discovery have, in the past, been focused on attempts to design antiproliferative agents, largely targeted to interfere with DNA integrity and replication. The malignant phenotype might be characterized by the emergence of cell populations with a greater survival potential: a lower proclivity to undergo apoptosis. This idea provides a possible explanation of the genesis and progression of cancer and of the inherent resistance of tumour cells to engage apoptosis. Work is described which identifies the molecular basis for differences in the survival potential of stem cells in the crypts of the colon and small intestine. The advantageous survival of colonic stem cells, provided by expression of bcl-2 and a muted p53 response to DNA damage, allows damaged cells to survive. Continued expression of bcl-2 renders tumour cells resistant to drug-induced DNA damage by a mechanism different from classical mechanisms of drug resistance. The attenuation of cell survival is described as a key component in strategies for the drug treatment of disseminated cancers.
CitationApoptosis and cancer chemotherapy. 1994, 345 (1313):319-25 Philos. Trans. R. Soc. Lond., B, Biol. Sci.
JournalPhilosophical Transactions of the Royal Society of London. Series B, Biological Sciences
- Apoptosis and cancer chemotherapy.
- Authors: Chresta CM, Arriola EL, Hickman JA
- Issue date: 1996 Oct
- Differential expression of bcl-2 in intestinal epithelia. Correlation with attenuation of apoptosis in colonic crypts and the incidence of colonic neoplasia.
- Authors: Merritt AJ, Potten CS, Watson AJ, Loh DY, Nakayama K, Nakayama K, Hickman JA
- Issue date: 1995 Jun
- Differential GADD45, p21CIP1/WAF1, MCL-1 and topoisomerase II gene induction and secondary DNA fragmentation after camptothecin-induced DNA damage in two mutant p53 human colon cancer cell lines.
- Authors: Goldwasser F, Bae I, Fornace AJ Jr, Pommier Y
- Issue date: 1996
- Bcl-XL small interfering RNA suppresses the proliferation of 5-fluorouracil-resistant human colon cancer cells.
- Authors: Zhu H, Guo W, Zhang L, Davis JJ, Teraishi F, Wu S, Cao X, Daniel J, Smythe WR, Fang B
- Issue date: 2005 Mar
- Expression of apoptosis-regulatory genes in lung tumour cell lines: relationship to p53 expression and relevance to acquired drug resistance.
- Authors: Reeve JG, Xiong J, Morgan J, Bleehen NM
- Issue date: 1996 May