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This finding implies that CRPC tissue acquires the ability to produce testosterone and DHT in an intracrine fashion, a finding which has been supported by further studies showing up-regulation of many of the steroid enzymes involved in androgen synthesis (see figure 1). For example, Stanbrough et al. analysed oligonucleotide microarrays from 33 CRPC bone metastasis samples and compared their gene expression with samples from 22 hormonesensitive primary cancers. The CRPC bone metastases demonstrated up-regulated expression of several enzymes involved in the steroid synthetic pathway: 17-beta hydroxysteroid dehydrogenase which converts androstenedione to testosterone; 3-beta hydroxysteroid dehydrogenase, which converts DHEA to androstenedione, and increased ratio of 5-alpha reductase isoform 1 to 2, which converts testosterone to DHT (Stanbrough M, et al 2006).

Accordingly, side effects of this medication include lethargy, rash, nausea, and liver toxicity. e. 20 mg in the morning, 10 mg in the evening) is required while patients are taking ketoconazole. Furthermore, given the relatively non-specific CYPP450 inhibition, ketoconazole interacts with a wide number of other medications. Its oral absorption and bioavailability can be variable, depending on the acidity of the stomach and fed/fasting state and use of acid suppressing medications. Despite these potential side effects and drug interactions, ketoconazole represents a viable and widely used secondary hormonal agent for CRPC, especially in the patient population Development of Novel Secondary Hormonal Therapies for Castrate-Resistant Prostate Cancer 31 with asymptomatic or minimally symptomatic bone-only metastatic or rising PSA-only disease.

J. Biol. Chem. 280, 40749-40756. , 2005b. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol. Pharmacol. 68, 10181030. , 2010. Impact on DNA methylation in cancer prevention and therapy by bioactive dietary components. Curr. Med. Chem. 17, 2141-2151. , 2009. Curcumin is a potent DNA hypomethylation agent. Bioorg. Med. Chem. Lett. 19, 706-709. , 2011. Integrating virtual screening and combinatorial chemistry for accelerated drug discovery. Comb. Chem.

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