Prostate cancer, advanced hormone-resistant

Mitoxantrone (Novantrone) is supplied for intravenous infusion. To induce remission in acute nonlymphocytic leukemia in adults, the drug is given in a daily dose of 12 mg/m for 3 days as a component of a regimen that also includes cytosine arabinoside. Mitoxantrone also is used in advanced hormone-resistant prostate cancer in a dose of 12 to 14 mg/m every 21 days. Mitoxantrone has been approved by the FDA for the treatment of late-stage, secondary progressive multiple sclerosis. 

Hoffmann J, Sommer A. Steroid hormone receptors as targets for the therapy of breast and prostate cancer— recent advances, mechanisms of resistance, and new approaches. J Steroid Biochem Mol Biol. 2005 93 191-200. 

Benzofurotriazoles 353 were prepared and their activity in the inhibition of CYP26A1 evaluated in a MCF-7 cell assay. These compounds are analogues of the advanced pharmaceutical candidate liarozole, 354 <2006MIP308-86>. CYP26A1 catalyzes the metabolism of all-/ra j retenoic acid (ATRA) and is believed to be principally responsible for controlling the levels of this retenoid. Elevated levels of ATRA are used to treat hormone refractory prostate cancer and psoriasis. It is hoped that inhibition of CYP26A1 will limit the development of resistance to these retinoid treatments. 

In 57 patients with advanced prostate cancer resistant to first-line hormonal therapy treated with estramustine and clodronate, the main adverse effect was nausea (33). Therapeutic efficacy was small. Reasons for premature withdrawal of clodronate in one study included refusal to continue treatment (five patients) and progressive disease of the bone (four patients) (34). One patient refused to take clodronate from the start seven discontinued clodronate after a median of 13 (range 0.2-23) months because of adverse events. In five patients the cause was nausea, combined with vomiting in four and diarrhea in one. After 0.9, 1.0, and 1.3 months the dosage of clodronate was reduced to 800mg/day in three patients (one had nausea, another dyspepsia, and a third had uncharacteristic sensations in the skeleton). 

Over expression of tumor suppressor gene bcI-2 plays an important role in cellular resistance to apoptosis caused by various factors (77). Lin et al have shown that over expression of anti-apoptotic Bcl-2 and Bc1-Xl proteins may play a role in the development of resistance to cancer therapy 18). Functional over expression of Bcl-2 has been reported to confer an anti-apoptotic potential in a variety of cell types. The role of Bcl-2 in epithelial cell-cycle control and in interactions with other cell-cycle regulators is not clearly understood. Its expression has been correlated with the hormone- and chemo-resistant phenotype in advanced prostate cancer 19). Granville et al have shown that overexpression of Bcl-2 in HL-60 cells prevented apoptosis-related events including caspase 3 and 6 activation, poly (ADP-ribose) polymerase cleavage by photodynamic therapy (20). Over expression of HER2 in estrogen receptor (ER)-positive human breast tumors has been associated with resistance to endocrine therapy. 

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