title: Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.
abstract: 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: 1n = 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 (150-300mg) 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 (9.1-1,839 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.
authors.affiliation: Princess Margaret Hospital, Toronto, Canada. pegoss@interlog.com
authors.forename: P E
authors.initials: PE
authors.lastname: Goss
authors.forename: K
authors.initials: K
authors.lastname: Strasser
authors.forename: R
authors.initials: R
authors.lastname: Marques
authors.forename: M
authors.initials: M
authors.lastname: Clemons
authors.forename: A
authors.initials: A
authors.lastname: Oza
authors.forename: R
authors.initials: R
authors.lastname: Goel
authors.forename: M
authors.initials: M
authors.lastname: Blackstein
authors.forename: L
authors.initials: L
authors.lastname: Kaizer
authors.forename: E E
authors.initials: EE
authors.lastname: Sterns
authors.forename: J M
authors.initials: JM
authors.lastname: Nabholtz
authors.forename: R
authors.initials: R
authors.lastname: De Coster
authors.forename: M
authors.initials: M
authors.lastname: Crump
authors.forename: M
authors.initials: M
authors.lastname: Abdolell
authors.forename: S
authors.initials: S
authors.lastname: Qi
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000097:blood; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D008875:Middle Aged; D009362:Neoplasm Metastasis; D017698:Postmenopause; D011788:Quality of Life; D051381:Rats; D011960:Receptors, Estrogen / Q000032:analysis; D013629:Tamoxifen / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007093:Imidazoles; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; C061121:liarozole