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High-dose oral tamoxifen, a potential multidrug-resistance-reversal agent: phase I trial in combination with
D L Trump1, D C Smith, P G Ellis
1Department of Medicine, Duke University Medical Center, Durham, N.C.
Background:
P-glycoprotein mediates resistance to natural-product anti-neoplastic agents like vinblastine through an active transport process resulting in reduced intracellular concentration of these agents. The triphenylethylene antiestrogen tamoxifen and its major metabolite N-desmethyltamoxifen at concentrations of 4-6 microM enhance the intracellular concentration of natural-product antineoplastics and augment the cytotoxicity of such drugs three-fold to 10-fold in a variety of human and murine cell lines.
Purpose:
On the basis of these preclinical findings, we conducted a phase I clinical trial of high-dose, oral tamoxifen administered in conjunction with a 5-day continuous infusion of vinblastine.
Methods:
We studied 53 patients with advanced epithelial tumors. Tamoxifen was given orally as a loading dose on day 1, followed by two doses a day on days 2-13. Vinblastine was given as a 120-hour continuous infusion (1.5 mg/m2 per day) on days 9-13 of each tamoxifen course. The starting dose of tamoxifen was 40 mg/m2 administered twice a day following a loading dose of 150 mg/m2. The maximum dose was 260 mg/m2 twice a day following a loading dose of 680 mg/m2. Treatment cycles were repeated every 28 days.
Results:
The dose-limiting toxic effects of tamoxifen were neurologic and began within 3-5 days after the start of treatment. They consisted of tremor, hyperreflexia, dysmetria, unsteady gait, and dizziness. One patient experienced a grand mal seizure 24 hours after the last tamoxifen dose. Toxic effects were rapidly reversible. Asymptomatic prolongation of the QT interval on electrocardiogram occurred at doses of tamoxifen of 80 mg/m2 or higher given twice a day. No coagulation or ophthalmologic abnormalities occurred. Tamoxifen did not enhance the toxicity of vinblastine. Mean plasma concentrations of tamoxifen or N-desmethyltamoxifen at 260 mg/m2 tamoxifen given twice a day for 13 days were 6.04 and 6.56 microM, respectively. There was no relationship between plasma antiestrogen content and the development of neurotoxic effects.
Conclusions:
Tamoxifen at 150 mg/m2 given twice a day following a loading dose of 400 mg/m2 results in plasma levels of tamoxifen and N-desmethyltamoxifen of 4 and 6 microM, respectively, without dose-limiting toxicity. We recommend this dose for phase II trials of tamoxifen to modulate P-glycoprotein-mediated drug resistance.
Implications:
Our study demonstrates that high-dose tamoxifen can be safely administered and that plasma concentrations that may inhibit P-glycoprotein function can be achieved.
Insights
High-dose tamoxifen with vinblastine shows promise in overcoming cancer drug resistance. This combination achieves plasma concentrations that may inhibit P-glycoprotein, enhancing chemotherapy effectiveness without significant added toxicity.
Area of Science:
- Oncology
- Pharmacology
- Drug Resistance
Background:
- P-glycoprotein (P-gp) confers resistance to natural-product antineoplastics like vinblastine by actively reducing intracellular drug concentrations.
- The antiestrogen tamoxifen and its metabolite N-desmethyltamoxifen can increase intracellular concentrations of natural antineoplastics.
- Preclinical data suggest tamoxifen augments antineoplastic cytotoxicity by 3- to 10-fold in various cell lines.
Purpose of the Study:
- To evaluate the safety and tolerability of high-dose oral tamoxifen combined with vinblastine in a Phase I clinical trial.
- To determine the maximum tolerated dose (MTD) of tamoxifen when administered with vinblastine.
- To assess the pharmacokinetic profile of tamoxifen and its metabolite during combination therapy.
Main Methods:
- A Phase I clinical trial involving 53 patients with advanced epithelial tumors.
- Tamoxifen administered orally (loading dose day 1, then twice daily days 2-13) concurrently with a 5-day continuous infusion of vinblastine (1.5 mg/m²/day).
- Tamoxifen doses escalated from 40 mg/m² twice daily to 260 mg/m² twice daily, with corresponding loading doses.
Main Results:
- Neurologic toxicities (tremor, hyperreflexia, unsteady gait) were dose-limiting for tamoxifen, appearing within 3-5 days and rapidly reversible.
- Asymptomatic QT interval prolongation occurred at tamoxifen doses of 80 mg/m² twice daily or higher.
- No enhanced vinblastine toxicity, coagulation, or ophthalmologic abnormalities were observed. Mean plasma concentrations of tamoxifen and N-desmethyltamoxifen reached 6.04 and 6.56 microM at the highest dose.
Conclusions:
- High-dose tamoxifen (150 mg/m² twice daily with a 400 mg/m² loading dose) achieves plasma levels of 4 and 6 microM for tamoxifen and N-desmethyltamoxifen, respectively, without dose-limiting toxicity.
- This dose is recommended for Phase II trials to modulate P-glycoprotein-mediated drug resistance.
- The study confirms safe administration of high-dose tamoxifen, achieving concentrations potentially inhibiting P-glycoprotein function.