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Mitochondrial Apoptosis: A New Foundation for Combining Agents in Prostate Cancer Treatment

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Final rept. 15 Feb 1999-14 Feb 2001

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After reviewing all of the drug combinations tested, the chemotherapeutic agent that illustrated the most promising synergy with other drugs was taxol. In particular, the combination of taxol with the HMG-CoA reductase inhibitor, mevastatin, and with the differentiating agent, phenylbutyrate, showed the most significant synergy. However, the combination of taxol with combination of mevastatin and phenylbutyrate showed no increase in antitumor efficacy compared with taxol plus mevastatin or taxol plus phenylbutyrate. These results make sense based on what is known about the mechanism of action of taxol, mevastatin, and phenylbutyrate. Ras, rho and related proteins play a critical role in signal transduction events regulating cell growth and motility. These proteins typically must undergo post translational modification involving the addition of either farnesol- or geranylgeranyl- groups. This reaction involves a condensation reaction between the protein and farnesol pyrophosphate or geranylgeranyl pyrophosphate. In this reaction, the pyrophosphate acts as a leaving group and resulting addition of farnesol- or genanylgeranyl to a cysteine on the protein. The farnesol- and geranylgeranyl groups are composed of isoprenyl- subunits. These isoprenyl subunits are synthesized from acetic acid by a pathway that starts with HMG-CoA reductase. Subsequent steps in the pathway include the formation of mevalonate, mevalonate 5-pyrophosphate and isopentenyl pyrophosphate. In addition to the formation of farnesyl pyrophosphate and geranylgeranyl pyrophosphate, isopentenyl pyrophosphate is an intermediate in the synthesis of a wide range of important molecules, including cholesterol, steroid hormones, and coenzyme QlO. Mevastatin, phenylbutyrate and taxol all inhibit separate steps along the pathway leading from acetate to the famesylation or geranylgeranylation of ras-like proteins.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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