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REVIEW ARTICLES

Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?

^a Membrane Biophysics Laboratory, Cardiovascular and Pulmonary Research Institute, Departments of Biochemistry and Medicine, MCP Hahnemann University School of Medicine, Allegheny Campus, Pittsburgh, Pennsylvania, USA

Manuscript received March 4, 1999; revised manuscript received June 24, 1999, accepted August 27, 1999.

Reprint requests and correspondence: Dr. R. Preston Mason, Director, Membrane Biophysics Laboratory, Allegheny General Hospital, 320 E. North Avenue, 2ST, Pittsburgh, Pennsylvania 15212-4772
mason{at}pgh.auhs.edu

Calcium channel blockers (CCBs) represent a chemically and pharmacologically diverse group of agents that are widely used for the treatment of hypertension and angina. A small number of retrospective, observational analyses have raised concern about a potential causal link between CCB use and an increased risk for cancer development. Despite the absence of cancer findings in extensive preclinical studies, it has been proposed that CCBs may work differently in humans by interfering with apoptosis, leading to an increased potential for abnormal cell proliferation and tumor growth. This biologic hypothesis has attracted considerable attention in the medical community but has not been critically evaluated. An analysis of the basic and clinical literature was conducted to examine biologic relationships among cell Ca²⁺ modulation, apoptosis, and cancer. In addition to a comprehensive review of the cellular and animal data, the results of large observational studies were included in this analysis. Results of this review demonstrated that the effects of CCBs on apoptosis are complex as both increases and decreases in intracellular Ca²⁺ have been linked to this form of programmed cell death. Most studies show that an effect (either positive or negative) of CCBs on apoptosis requires doses in the supra-pharmacologic range, and are therefore not clinically relevant. Results of large and methodologically robust observational studies fail to provide support for the hypothesis that CCB use is associated with an increased susceptibility for cancer incidence. A comprehensive analysis of the basic and clinical evidence does not support a causal relationship between the therapeutic use of CCBs and an increased incidence of cancer development as a result of interfering with apoptosis.

Abbreviations and Acronyms   Ca2+ = calcium   CCB = calcium channel blocker   RR = relative risk   TUNEL = terminal deoxynucleotide transferase-mediated dUTP-biotin nick end labeling

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