Evaluation of toremifene for reversal of multidrug resistance in renal cell cancer patients treated with vinblastine

• Published in: Cancer chemotherapy and pharmacology Vol. 46; no. 1; pp. 27 - 34
• Main Authors: BRAYBROOKE, J. P, VALLIS, K. A, HOULBROOK, S, ROCKETT, H, ELLMEN, J, ANTTILA, M, GANESAN, T. S, HARRIS, A. L, TALBOT, D. C
• Format: Journal Article
• Language: English
• Published: Berlin Springer 2000
• Subjects: Administration, Oral; Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Hormonal - administration & dosage; Antineoplastic Agents, Hormonal - blood; Antineoplastic Agents, Hormonal - therapeutic use; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - metabolism; Chemotherapy; Drug Administration Schedule; Drug Resistance, Multiple; Female; Fluorescent Dyes - pharmacokinetics; Humans; Kidney Neoplasms - drug therapy; Kidney Neoplasms - metabolism; Male; Medical sciences; Middle Aged; Orosomucoid - metabolism; Pharmacology. Drug treatments; Protein Binding; Rhodamine 123 - pharmacokinetics; Tamoxifen - analogs & derivatives; Tamoxifen - blood; Toremifene - administration & dosage; Toremifene - blood; Toremifene - therapeutic use; Vinblastine - administration & dosage; Vinblastine - therapeutic use; Kidney disease; Antineoplastic agent; Human; Drug combination; Urinary system disease; Vinblastine; Toxicity; P Glycoprotein; Malignant tumor; Kidney; Alkaloid; Chemotherapy; Biological fixation; Reversion; Treatment; Multiple resistance; α1-acid-Glycoprotein; Toremifene; Pharmacokinetics; High dose
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s002809900085

Expression of P-glycoprotein (Pgp), which confers the multidrug resistance (MDR) phenotype, is thought to contribute to the insensitivity of renal cell cancer (RCC) to chemotherapy. The development of Pgp inhibitors for clinical application has been hampered by unacceptable toxicity at doses required to achieve adequate cellular concentration. Toremifene is able to reverse MDR and sensitise RCC to vinblastine in vitro. However, in vivo toremifene is tightly bound to serum proteins, in particular the acute phase protein alpha1-acid glycoprotein (AAG), which may limit tissue availability. In this phase I-II study we assessed the tolerability of short courses of high dose toremifene in combination with vinblastine and evaluated the key determinants of MDR reversal in vivo.
Twenty-seven patients with metastatic RCC received escalating doses of oral toremifene for 3 days every 2 weeks in combination with vinblastine 6 mg/m2 i.v. on day 3 of each cycle. The serum concentration of toremifene, its metabolites and AAG were measured and the effect of patients' serum on inhibition of Pgp in vitro was determined.
Twenty-six patients were evaluable for response. Eight patients (31%) had stable disease and 18 patients (69%) progressive disease. The mean serum concentration of toremifene at 780 mg daily for 3 days was 7.82 microM [standard deviation (SD) 2.48, range 2.50 to 14.70], which exceeds that known to reverse MDR in vitro. The serum concentration of the major metabolite of toremifene, N-demethyltoremifene, which also reverses MDR, was 5.13 microM (SD 1.78, range 1.80 to 9.00). In 60% of patients the pre-treatment AAG concentration was above that known to block the effects of toremifene in vitro. However, addition of serum from patients on toremifene to MCF-7 adr cells in vitro inhibited Pgp-mediated efflux of rhodamine 123.
We have shown that short course, high-dose toremifene in combination with vinblastine is generally well tolerated and that the concentration of toremifene required to reverse MDR in vitro is achievable in vivo.