fenretinide and Acute-Disease

N-(4-hydroxyphenyl) retinamide (Fenretinide, 4-HPR) inhibits cell growth by inducing apoptosis in numerous tumor cell types including all-trans-retinoic acid (ATRA)-resistant tumor cells. However, the mechanism(s) by which 4-HPR mediates its anti-proliferative effects remains unclear. Here, we determined whether 4-HPR induced growth inhibition and gene expression involve retinoid receptors in human acute myeloid leukemia (AML) cells (HL-60). We treated HL-60 and ATRA-resistant HL-60 (HL-60R) cells that express mutated RARalpha and very low levels of RARbeta, RARgamma and RXRalpha with 4-HPR (2 microM) for 3 days. 4-HPR showed significant anti-proliferative effects against both cell types and induced growth inhibition (92.7%) in HL-60 cells. However, at the same dose, 4-HPR induced only 53.4% growth inhibition in HL-60R cells. Growth inhibition by 4-HPR was significantly enhanced in HL-60R cells that were retroviraly transduced to express human RARalpha, RARbeta or RXRalpha (95.6%, 97.1%, and 75.6%, respectively), in comparison to HL-60R cells (P < 0.05), but not in HL-60R cells expressing RARgamma. Although ATRA and 4-HPR induced expression of CYP26, an ATRA-inducible gene encoding a cytochrome P450 enzyme, in HL-60 cells, both retinoids failed to induce CYP26 in HL-60R cells. However, induction of CYP26 mRNA by 4-HPR was restored in HL-60R cells expressing RARalpha and RARgamma, but not RARbeta and RXRalpha. In conclusion, our data suggest that nuclear retinoid receptors are involved in 4-HPR-induced growth inhibition and gene expression, and that 4-HPR can mediate its anti-proliferative effects through retinoid receptor-dependent mechanisms in HL-60 cells.

Topics: Acute Disease; Cell Proliferation; Cytochrome P-450 Enzyme System; Fenretinide; Gene Expression Regulation, Neoplastic; HL-60 Cells; Humans; Leukemia, Myeloid; Receptors, Retinoic Acid; Retinoic Acid 4-Hydroxylase; Retinoic Acid Receptor alpha; Retinoic Acid Receptor gamma; Retinoid X Receptor alpha; RNA, Messenger

To determine the activity of fenretinide in patients with myelodysplastic syndromes, 15 patients were treated (300 mg/d starting dose, escalated to 400 mg/d) for a 12-week course. No responses were observed in 14 evaluable patients. Exacerbation of thrombocytopenia occurred in one patient with chronic myelomonocytic leukemia, who succumbed to an intracerebral hemorrhage after 3 weeks of treatment. Two patients with long-standing stable sideroblastic anemia experienced interval leukemic progression. In one patient, clinical features of chronic myelomonocytic leukemia appeared, characterized by a striking rise in peripheral monocyte count (0.49 x 10(9)/l to 10.8 x 10(9)/l) and hepatosplenomegaly, which resolved promptly after cessation of treatment. The second patient experienced evolution into acute myelomonocytic leukemia with cytogenetic progression. The drug was well tolerated with no patient having to discontinue treatment because of toxicity. We conclude that fenretinide lacks clinical efficacy in the treatment of myelodysplasia and in some patients may enhance leukemic progression.

Topics: Acute Disease; Aged; Cerebral Hemorrhage; Drug Evaluation; Fenretinide; Humans; Leukemia; Leukocytosis; Male; Middle Aged; Monocytes; Myelodysplastic Syndromes; Thrombocytopenia; Tretinoin