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Apoptosis and cancer chemotherapy
J A Hickman1, C S Potten, A J Merritt
1Cancer Research Campaign Molecular and Cellular Pharmacology Group, School of Biological Sciences, University of Manchester, U.K.
Abstract:
The 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.
Insights
Cancer drug resistance stems from tumor cells
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Disseminated cancers often exhibit resistance to systemic therapies, posing a significant clinical challenge.
- Traditional drug discovery has focused on antiproliferative agents targeting DNA, but this has limited success against resistant tumors.
- Tumor cell resistance may arise from enhanced survival mechanisms, specifically a reduced tendency to undergo programmed cell death (apoptosis).
Purpose of the Study:
- To investigate the molecular basis of differential survival potential in intestinal stem cells.
- To elucidate the role of specific genes, such as bcl-2 and p53, in cancer cell survival and drug resistance.
- To identify novel therapeutic strategies targeting cell survival pathways for overcoming drug resistance in disseminated cancers.
Main Methods:
- Comparative analysis of stem cell survival mechanisms in the colon and small intestine.
- Molecular investigation of gene expression patterns, including bcl-2 and p53.
- Assessment of drug resistance mechanisms in tumor cells related to apoptosis regulation.
Main Results:
- Colonic stem cells exhibit enhanced survival due to bcl-2 expression and a blunted p53 response to DNA damage.
- This survival advantage allows damaged cells to persist, contributing to cancer development and progression.
- Sustained bcl-2 expression in tumor cells confers resistance to drug-induced DNA damage via non-classical pathways.
Conclusions:
- The inherent resistance of disseminated cancers is linked to tumor cells' enhanced survival potential and evasion of apoptosis.
- Targeting and attenuating cancer cell survival mechanisms represents a promising strategy for improving drug treatment efficacy.
- Understanding the molecular underpinnings of bcl-2 and p53 in cancer cell survival is crucial for developing next-generation cancer therapies.