Phase I study of vinblastine and verapamil given by concurrent Iv infusion

A. B. Benson, D. L. Trump, J. M. Koeller, M. I. Egorin, E. A. Olman, R. S. Witte, T. E. Davis, D. C. Tormey

Research output: Contribution to journalArticle

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Abstract

Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion x 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs <2000/mm3, and two of 17 patients platelet count nadirs <100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 μM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

Original languageEnglish (US)
Pages (from-to)795-799
Number of pages5
JournalCancer Treatment Reports
Volume69
Issue number7-8
StatePublished - Nov 28 1985

Fingerprint

Vinblastine
Verapamil
Anthracyclines
Vinca Alkaloids
Active Biological Transport
Leukemia P388
Ehrlich Tumor Carcinoma
Heart Block
Calcium Channel Blockers
Platelet Count
Ultrasonics
Stroke Volume
Electrocardiography
Maintenance
Blood Pressure
Drug Therapy
Pharmaceutical Preparations
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Benson, A. B., Trump, D. L., Koeller, J. M., Egorin, M. I., Olman, E. A., Witte, R. S., ... Tormey, D. C. (1985). Phase I study of vinblastine and verapamil given by concurrent Iv infusion. Cancer Treatment Reports, 69(7-8), 795-799.
Benson, A. B. ; Trump, D. L. ; Koeller, J. M. ; Egorin, M. I. ; Olman, E. A. ; Witte, R. S. ; Davis, T. E. ; Tormey, D. C. / Phase I study of vinblastine and verapamil given by concurrent Iv infusion. In: Cancer Treatment Reports. 1985 ; Vol. 69, No. 7-8. pp. 795-799.
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Benson, AB, Trump, DL, Koeller, JM, Egorin, MI, Olman, EA, Witte, RS, Davis, TE & Tormey, DC 1985, 'Phase I study of vinblastine and verapamil given by concurrent Iv infusion', Cancer Treatment Reports, vol. 69, no. 7-8, pp. 795-799.

Phase I study of vinblastine and verapamil given by concurrent Iv infusion. / Benson, A. B.; Trump, D. L.; Koeller, J. M.; Egorin, M. I.; Olman, E. A.; Witte, R. S.; Davis, T. E.; Tormey, D. C.

In: Cancer Treatment Reports, Vol. 69, No. 7-8, 28.11.1985, p. 795-799.

Research output: Contribution to journalArticle

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T1 - Phase I study of vinblastine and verapamil given by concurrent Iv infusion

AU - Benson, A. B.

AU - Trump, D. L.

AU - Koeller, J. M.

AU - Egorin, M. I.

AU - Olman, E. A.

AU - Witte, R. S.

AU - Davis, T. E.

AU - Tormey, D. C.

PY - 1985/11/28

Y1 - 1985/11/28

N2 - Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion x 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs <2000/mm3, and two of 17 patients platelet count nadirs <100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 μM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

AB - Overcoming resistance to chemotherapy is an important goal in cancer treatment. In many systems, resistance to anthracyclines and vinca alkaloids correlates with a diminished intracellular content of drug. In P388 leukemia and Ehrlich ascites tumor, an active outward transport of anthracyclines and vinca alkaloids occurs. Calcium channel blockers, such as verapamil, inhibit this active outward transport and increase intracellular content of vinblastine and anthracyclines in cells resistant to vinca alkaloids and anthracyclines, respectively. We report a phase I trial of vinblastine (1.5 mg/m2 daily as iv continuous infusion x 5 days) in 17 patients and concurrent verapamil in escalating doses. Verapamil was administered as a loading dose (0.02-0.1 mg/kg) followed by a maintenance infusion (0.036-0.18 mg/kg/hour) for 5 1/2 days with continuous cardiac monitoring. There was no apparent augmentation of vinblastine toxicity when vinblastine and verapamil were given concurrently. ECG change was the dose-limiting toxicity. At 0.12 mg/kg/hour, five of nine patients developed first-degree heart block (mean P-R interval, 0.32 seconds; range, 0.23-0.52 seconds). Junctional rhythms were noted in two of 17 patients. Reversible nonspecific T-wave changes were seen in four of 17 patients. Blood pressure and left ventricular ejection fractions (ultrasonic) were not altered. Five of 17 patients had wbc count nadirs <2000/mm3, and two of 17 patients platelet count nadirs <100,000/mm3. Four patients experienced neurotoxicity. A mean vinblastine concentration of 2.2 ng/ml (0.55 nM) and a mean verapamil concentration of 290 ng/ml (0.45 μM) were achieved with the concurrent 5-day infusion. The tolerable levels of verapamil obtained appear to be less than those which were reported to inhibit vinblastine efflux in vitro. Additional in vitro experiments at the tolerable doses of vinblastine and verapamil are recommended.

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Benson AB, Trump DL, Koeller JM, Egorin MI, Olman EA, Witte RS et al. Phase I study of vinblastine and verapamil given by concurrent Iv infusion. Cancer Treatment Reports. 1985 Nov 28;69(7-8):795-799.