Role of apoptotic response in cellular resistance to cytotoxic agents

doi:10.1016/S0163-7258(97)00086-7

Pharmacology & Therapeutics

Volume 76, Issues 1–3, October–December 1997, Pages 177-185

https://doi.org/10.1016/S0163-7258(97)00086-7 Get rights and content

Abstract

The development of drug resistance is a major obstacle to effectiveness of chemotherapeutic treatment of human tumors with cytotoxic agents. Drug resistance is described as a multifactorial phenomenon, involving the expression of defense factors and/or detoxification mechanisms, alterations in drug-target interactions, and cellular response to specific cytotoxic lesions (in particular, DNA damage). Although the proposed mechanisms may contribute to the development of a variable degree of cellular resistance, it is possible that the cell response (i.e., DNA repair or apoptosis) following DNA damage plays a critical role in determining cellular chemosensitivity. The preclinical observations that tumor response to effective drug treatments is associated with induction of apoptosis support the possibility that a decreased susceptibility to apoptosis (apoptosis resistance) is relevant to clinical resistance. A number of molecular alterations associated with transformation and/or tumor progression may also be implicated in regulation of cell death pathways and in the development of drug resistance. There is evidence that the wild-type p53 is involved in cellular response to DNA damage, including cell cycle regulation, DNA repair, and activation of the pathway leading to apoptosis. Loss of wild-type p53 function could cause resistance to DNA-damaging agents, as a consequence of abrogation of p53-dependent apoptosis. The identification of new agents able to trigger p53-independent apoptosis and the search for biochemical modulators downstream of p53 may be of clinical relevance because many tumors are deficient in p53 function due to mutation or deletion. An overview of the resistance mechanisms is presented, with particular reference to the role of p53 mutations in clinical resistance and of apoptosis-related genes in cellular chemosensitivity.

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Role of apoptotic response in cellular resistance to cytotoxic agents

Abstract

Blood

Blood

Trends Genet.

Eur. J. Cancer

J. Biol. Chem.

Lancet

Eur. J. Cancer

Cell

Blood

Blood

Specific p53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients

Nat. Med.

A doxorubicin disaccharide analog: apoptosis-related improvement of efficacy in vivo

J. Natl. Cancer Inst.

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J. Exp. Med.

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Cancer Res.

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Br. J. Cancer

Apoptosis as a determinant of tumor sensitivity to topotecan in human ovarian tumors: preclinical in vitro/in vivo studies

Clin. Cancer Res.

Bcl-xL and bcl-2 repress a common pathway of cell death

J. Exp. Med.

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Mol. Pharmacol.

Bax independent inhibition of apoptosis by Bcl-xL

Nature

p53 and treatment of bladder cancer

Nature

Lonidamine induces apoptosis in drug-resistant cells independently of the p53 gene

J. Clin. Invest.

Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial

J. Clin. Oncol.

The control of apoptosis and drug resistance in ovarian cancer: influence of p53 and bcl-2

Oncogene

p53 gene mutations are associated with decreased sensitivity of human lymphoma cells to DNA damaging agents

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Disruption of p53 function sensitizes breast cancer MCF-7 cells to cisplatin and pentoxifylline

Cancer Res.

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Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis

Cancer Res.

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Taxol induces bcl-2 phosphorylation and death of prostate cancer cells

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Cancer Res.

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Bax independent inhibition of apoptosis by Bcl-x_L