Safety and efficacy of weekly oral oltipraz in chronic smokers.

Cigarette smoking is thought to contribute to carcinogenesis by formation of DNA adducts of tobacco smoke constituents leading to genotoxic damage. The dithiolethione, oltipraz, is a putative cancer chemopreventive agent that induces phase II detoxifying enzymes in preclinical models and reduces aflatoxin adducts in humans living in areas with high dietary levels. To determine if oltipraz could reduce adduct levels of tobacco smoke constituents in the lungs and other target organs, chronic smokers were enrolled to one of three arms: 400 or 200 mg/wk oral oltipraz or placebo. Endobronchial tissue and bronchoalveolar lavage were done before and after 12 weeks of drug treatment; peripheral blood, urine, and oral saline rinse were also collected. Toxicity was assessed every 4 weeks. Fifty-nine of the 77 enrolled subjects completed the study. Of those receiving oltipraz, 15% experienced grade 2/3 toxicity, which was predominantly gastrointestinal. All subject withdrawals occurred in the oltipraz groups. There was no significant difference between pre- and post-polycyclic aromatic hydrocarbon-DNA adduct levels in lung epithelial cells measured by immunoperoxidase staining between treatment and placebo groups. Likewise, no significant differences were found in polycyclic aromatic hydrocarbon or benzo(a)pyrene-7,8-diol-9,10-epoxide adducts measured in blood, oral lining cells, or bladder lining cells. There was also no increase in mRNA or enzymatic activity of phase II enzymes and no change in glutathione levels. Thus, despite moderate drug-related toxicity, there was no significant effect on pharmacodynamic or surrogate risk biomarkers. Other agents with lower toxicity and greater activity to induce phase II enzymes are needed to definitively test the detoxification-induction paradigm in smokers.

Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.

Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C(max)) ranged between 4.3 and 16.3 micro M for total genistein and 0.066 and 0.17 micro M for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.

Phase II study of mitoxantrone and ketoconazole for hormone-refractory prostate cancer.

BACKGROUND: Doxorubicin plus ketoconazole has exhibited significant activity in patients with advanced prostate cancer. However, overall and cardiac-specific toxicity was reported to be high. Mitoxantrone has activity similar to that of doxorubicin, is less cardiotoxic, and is widely used to treat prostate cancer. The current study sought to evaluate the toxicity and activity of mitoxantrone plus ketoconazole in a cohort of patients with hormone-refractory prostate cancer. METHODS: Progression after medical or surgical castration and, for those patients receiving antiandrogens, progression after withdrawal was required, as was objective evidence of metastasis, castrate levels of testosterone, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2, and intact cardiac function. After enrollment onto a multicenter local consortium study, subjects were treated with mitoxantrone at a dose of 12 mg/m2 intravenously every 3 weeks plus continuous oral ketoconazole at a dose of 400 mg 3 times daily and ascorbic acid at a dose of 250 mg. Replacement doses of hydrocortisone were given. RESULTS: For 40 enrolled subjects, the median prostate-specific antigen and ECOG performance status were 68 and 1, respectively, 53% had Gleason scores of 8 to 10, and all had metastasis. Predominant Grade 3/4 toxicities were: neutropenia in 13%, neutropenic fever in 10%, and anemia in 13%. Of 37 evaluable patients, 8% achieved a complete remission (CR) and 62% achieved a partial remission (PR), for a CR plus PR rate of 70%. For soft tissue and bone disease, overall response rates were 13% and 8%, respectively. The median progression-free survival and overall survival were 10 months and 18 months, respectively. CONCLUSIONS: Mitoxantrone plus ketoconazole is well tolerated, is active in hormone-refractory prostate cancer, and should be studied further.