Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advancedmalignancies

Citation
Rs. Dipaolo et al., Phase I clinical and pharmacologic study of 13-cis-retinoic acid, interferon alfa, and paclitaxel in patients with prostate cancer and other advancedmalignancies, J CL ONCOL, 17(7), 1999, pp. 2213-2218
Citations number
26
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
JOURNAL OF CLINICAL ONCOLOGY
ISSN journal
0732-183X → ACNP
Volume
17
Issue
7
Year of publication
1999
Pages
2213 - 2218
Database
ISI
SICI code
0732-183X(199907)17:7<2213:PICAPS>2.0.ZU;2-K
Abstract
Purpose: Recent studies demonstrate that retinoids decrease expression of t he anti-apoptotic protein bcl-2, enhance the effect of chemotherapy, and ac t synergistically with interferon alfa (IFN alpha) to inhibit tumor cell gr owth in vitro, A phase I trial of 13-cis-retinoic acid (CRA), IFN alpha, an d paclitaxel (TAX) was conducted to determine the toxicity and recommended phase II dose of this combination, Pharmacodynamic studies were performed t o determine whether CRA and IFN alpha could modulate bcl-2 expression in vi tro and in patients. Patients and Methods: Twenty-two patients with prostate cancer or other adv anced malignancies were treated with CRA/IFN alpha and escalating doses of TAX. The effect of CRA/IFN alpha on TAX pharmacokinetics was analyzed in ha th patients and human liver microsomes, the effect of CRA/IFN alpha on bcl- 2 expression was assessed in vitro and in peripheral-blood mononuclear cell s (PBMCs) by immunoblotting, Results: CRA 1 mg/kg on days 1 to 4, IFN alpha 6 MU/m(2) subcutaneously on days 1 to 4, and TAX 175 mg/m(2) on day 3 was well tolerated, pharmacokinet ic studies demonstrated that CRA/IFN alpha caused a 33% decrease in TAX cle arance and a 23% decrease in the area under the concentration-rime curve va lves of the TAX metabolite 6-alfa-hydroxytaxol (6-HT). CRA alone reduced co nversion of TAX to 6-HT by 41% in human liver microsomes. CRA/IFN alpha dec reased bcl-2 expression in vitro and in PBMCs. Conclusion: CRA/IFN alpha and TAX is a well-tolerated regimen. CRA/IFN alph a increases TAX area under the concentration-time curve through an inhibito ry effect of CRA on the metabolism of TAX to 6-HT. CRA/IFN alpha can modula te bcl-2 expression in vitro and demonstrates similar biologic activity in patients. Further studies will determine the activity of CRA/IFN alpha/TAX and validate the assessment of bcl-2 in PBMCs as a marker of tumor response , (C) 1999 by American Society of Clinical Oncology.