Liarozole Fumarate (R85246): In the Treatment of ER Negative, Tamoxifen Refractory or Chemotherapy Resistant Postmenopausal Metastatic Breast Cancer.

Autor: Goss, Paul, Strasser, Kathrin, Marques, Ricardo, Clemons, Mark, Oza, Amit, Goel, Rakesh, Blackstein, Martin, Kaizer, Leonard, Sterns, Ernest, Nabholtz, Jean-Marc, Coster, Roland, Crump, Michael, Abdolell, Mohamed, Qi, Shangle
Zdroj: Breast Cancer Research & Treatment; Nov2000, Vol. 64 Issue 2, p177-188, 12p
Abstrakt: Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1; n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150–300 mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0–52.3%; median duration (MD) 20 months; range 2–36.5); 25% in group 2 (95% CI 11.0–52.3%; MD 6.5 months; range 3.5–38); 11% in group 3 (95% CI 4.2–29.2%; MD 7 months; range 3–8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1–1839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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