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