Continuation of PROSTATE CANCER: LATE STAGE
Other Anticancer Effects of Nizoral
Nizoral possesses other anti-cancer properties independent of its testosterone-lowering effects. In laboratory studies, Nizoral showed synergistic (more than additive) cell-killing effects when used with the chemotherapy drugs vinblastine (Velban) and etoposide (VePesid) in cancer cell cultures (Eichenberger et al., Clin. Invest. Med., 1989).
Nizoral acts on cytochrome P-450-dependent 14-demethylation, and decreases conversion of lanosterol to cholesterol, and blocks 17,20-desmolase (or lyase), resulting in a decrease in serum T, androstenedione, and dehydroepiandrosterone (DHEA). Twenty-four-hour urinary free cortisol is reduced 25% but still remains within the range of normal, as mentioned above. Recent studies indicate that Nizoral also blocks 17a-hydroxylase.
Velban is an active agent in AIPC and is used with Nizoral, doxorubicin (Adriamycin), and estramustine (Emcyt) in the "Logothetis protocol." Nizoral also has a direct cytotoxic effect on the PC cell (see figure below). In two human cell lines of AIPC, PC-3, and DU-145, Nizoral had direct cell-killing effects at serum values that were attainable with oral doses used clinically, as shown on the following page (1.1 to 10.0 mcg/ml) (Eichenberger et al., J. Urol., 1989).
Nizoral has additional anticancer effects. It has been proven to block the multidrug resistance (MDR) gene that is largely responsible for cancer cells developing resistance to many types of chemotherapy drugs. In a 1994 paper by Siegsmund et al., Nizoral added to in vitro cancer cell cultures was effective in overcoming MDR to Velban and Adriamycin (Siegsmund et al., J. Urol., 1987).
Nizoral and HC in AIPC
Published clinical trials of Nizoral involved studies in the pre-PSA era. In the current era, PSA is used as a surrogate biomarker of disease response. In the pre-PSA era, Pont et al. (J. Urol., 1987) reported an 88% decrease or disappearance in pain in 17 previously untreated men with metastatic PC. Two of these patients remained in complete remission with no evidence of disease after 30 months of treatment.
Muscato et al. (Proc. Am. Soc. Clin. Oncol., 1994) reported results with Nizoral + HC in 21 patients considered hormone-refractory. Seven (33%) of 21 patients had a greater than 90% fall in PSA, with six of these seven maintaining remissions lasting longer than 12 months (range 14 to 35+ months). Muscato et al. emphasized the importance of an acid environment for proper absorption, the avoidance of taking Nizoral with food, as well as the importance of making sure patients are not taking H2-blockers, Carafate, and/or antacids. Muscato et al. pointed out that H2-blockers (Zantac, Tagamet, Axid, Pepcid) or proton pump inhibitors (such as Prilosec or Prevacid) can decrease the absorption of Nizoral by as much as 75%. Therefore, Nizoral plus HC may be one of the most active regimens for AIPC.
In a recent paper, Small et al. (J. Urol., 1997) reported the results of Nizoral plus HC therapy in men with progressive disease on ADT and after anti-androgen withdrawal. Of 48 evaluable patients, 30 (63%) had a PSA decrease of greater than 50% for at least 8 weeks, while 23 of these (48%) had a decrease in PSA of greater than 80% for at least 8 weeks. For all patients, the median PSA decrease was 79% (range 0 to 99%). The median duration of response was 3.5 months, with 23 of the 48patients having ongoing responses (range 3.3+ months to 12.8+ months). No difference was seen in response rates despite the presence or absence of an AAWR. The median survival of all patients had not been reached at 6+ months.
In another report, Small et al. (Cancer, 1997) treated 20 consecutive patients with simultaneous antiandrogen withdrawal and Nizoral + HC. The median PSA at entry was 13 ng/mL (range 1.9 to 1000 ng/mL). Eleven of 20 patients (55%) met their criteria for response, i.e., a greater than 50% decline from baseline PSA. The median duration of response was 8.5 months (95% confidence interval 7 to 17 months), and the median overall survival was 19 months. Due to its effects on the MDR gene, Nizoral has been studied in combination with chemotherapy.
Continuation of PROSTATE CANCER: LATE STAGE