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Phase I Clinical and Pharmacologic Study of 13-cis-Retinoic Acid, Interferon Alfa, and Paclitaxel in Patients With Prostate Cancer and Other Advanced Malignancies

From the Departments of Medicine and Pharmacology, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School; The Cancer Institute of New Jersey; and Rutgers University College of Pharmacy, New Brunswick, NJ.

Address reprint requests to Robert S. DiPaola, MD, Division of Medical Oncology, The Cancer Institute of New Jersey, 195 Little Albany St, New Brunswick, NJ 08901; email dipaolrs{at}umdnj.edu

PURPOSE: Recent studies demonstrate that retinoids decrease expression of the anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and act synergistically with interferon alfa (IFN) to inhibit tumor cell growth in vitro. A phase I trial of 13-cis-retinoic acid (CRA), IFN, and paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination. Pharmacodynamic studies were performed to determine whether CRA and IFN could modulate bcl-2 expression in vitro and in patients.

PATIENTS AND METHODS: Twenty-two patients with prostate cancer or other advanced malignancies were treated with CRA/IFN and escalating doses of TAX. The effect of CRA/IFN on TAX pharmacokinetics was analyzed in both patients and human liver microsomes. The effect of CRA/IFN on bcl-2 expression was assessed in vitro and in peripheral-blood mononuclear cells (PBMCs) by immunoblotting.

RESULTS: CRA 1 mg/kg on days 1 to 4, IFN 6 MU/m² subcutaneously on days 1 to 4, and TAX 175 mg/m² onday 3 was well tolerated. Pharmacokinetic studies demonstrated that CRA/IFN caused a 33% decrease in TAX clearance and a 23% decrease in the area under the concentration-time curve values of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced conversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFN decreased bcl-2 expression in vitro and in PBMCs.

CONCLUSION: CRA/IFN and TAX is a well-tolerated regimen. CRA/IFN increases TAX area under the concentration-time curve through an inhibitory effect of CRA on the metabolism of TAX to 6-HT. CRA/IFN can modulate bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFN/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response.

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