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Modulation of vinblastine resistance with cyclosporine: a phase I study
B L Samuels1, R Mick, N J Vogelzang
1Section of Hematology/Oncology, University of Chicago, IL.
Objective:
Tumor cell resistance is a major cause of failure to cure advanced malignancies. Multidrug resistance is thought to be an important mechanism of such resistance. Our aims were to identify doses of cyclosporine that would achieve blood levels effective in modulating multidrug resistance to vinblastine and to evaluate the toxicities and maximum tolerated dose of cyclosporine when administered in conjunction with vinblastine.
Methods:
We conducted a phase I trial of vinblastine and escalating doses of cyclosporine. Cyclosporine was given by continuous intravenous infusion over 120 hours and vinblastine was administered by continuous infusion from hour 12 to hour 108. Sixty-two patients entered the trial, of whom 60 were evaluable.
Results:
Cyclosporine was escalated from 1 to 15.6 mg/kg/day. Vinblastine doses were reduced to 1.6 and then 1.2 mg/m2/day because of increasing vinblastine toxicity at higher cyclosporine doses. The maximum tolerated dose of cyclosporine at 1.2 mg/m2/day vinblastine was 12.5 mg/kg/day; at this dose level, mean blood cyclosporine level was 1.25 +/- 0.41 mumol/L. Significant nephrotoxicity was observed at higher cyclosporine doses in two of four patients. Nephrotoxicity was not significant at doses at or lower than this maximum tolerated dose and was not cyclosporine dose dependent. Myelosuppression, neurotoxicity, and transient hyperbilirubinemia were observed and were cyclosporine dose dependent. CONCLUSIONS. Cyclosporine by continuous infusion may be safely given in high doses concurrently with continuous-infusion vinblastine. Plasma levels of cyclosporine > or = 1 mumol/L can be sustained during vinblastine administration. No sustained effect on T-cell subsets was observed. Vinblastine toxicity is enhanced by cyclosporine in a dose-dependent fashion and correlates with cyclosporine-induced hyperbilirubinemia.
Insights
High doses of cyclosporine can be safely given with vinblastine to overcome tumor resistance. This combination enhances vinblastine toxicity, which is dose-dependent and linked to cyclosporine levels.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Tumor cell resistance, particularly multidrug resistance, is a primary obstacle in treating advanced cancers.
- Identifying effective strategies to overcome drug resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To determine safe and effective doses of cyclosporine for modulating multidrug resistance to vinblastine.
- To evaluate the toxicities and maximum tolerated dose of cyclosporine when co-administered with vinblastine.
Main Methods:
- A Phase I clinical trial involving escalating doses of cyclosporine administered via continuous intravenous infusion (120 hours).
- Vinblastine was given via continuous infusion (from hour 12 to 108) concurrently with cyclosporine.
- Sixty-two patients with advanced malignancies were enrolled, with 60 evaluable for toxicity and response.
Main Results:
- The maximum tolerated dose of cyclosporine was 12.5 mg/kg/day when combined with vinblastine at 1.2 mg/m2/day, achieving mean blood cyclosporine levels of 1.25 ± 0.41 μmol/L.
- Vinblastine doses were reduced due to toxicity at higher cyclosporine levels.
- Cyclosporine-induced dose-dependent myelosuppression, neurotoxicity, and hyperbilirubinemia were observed; significant nephrotoxicity occurred at higher doses in a subset of patients.
Conclusions:
- Continuous infusion cyclosporine can be safely administered at high doses with continuous infusion vinblastine.
- Sustained plasma cyclosporine levels ≥ 1 μmol/L are achievable during vinblastine therapy.
- Cyclosporine enhances vinblastine toxicity in a dose-dependent manner, correlating with hyperbilirubinemia, but does not appear to affect T-cell subsets long-term.