Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil

Sabine C. Linn, Coenraad K. Van Kolken, Olaf Van Tellingen, Paul Van Der Valk, Cornelis J. Van Groeningen, Catharina M. Kuiper, Herbert M. Pinedo, Giuseppe Giaccone

Research output: Contribution to journalArticle

Abstract

Purpose: To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue. Patients and Methods: Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (IV) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay. Results: The bepridil plasma level was greater than 2 μmol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QT(c)-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone. Conclusion: Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.

Original languageEnglish (US)
Pages (from-to)812-819
Number of pages8
JournalJournal of Clinical Oncology
Volume12
Issue number4
StatePublished - Apr 1994
Externally publishedYes

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Bepridil
Vinblastine
Multiple Drug Resistance
P-Glycoprotein
Colorectal Neoplasms
Drug Resistance
Neoplasms
Central Venous Catheters
Calcium Channel Blockers
Drug Combinations
Ribonucleases
Clinical Studies
Antineoplastic Agents
Pharmacokinetics
Immunohistochemistry
Gene Expression

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Linn, S. C., Van Kolken, C. K., Van Tellingen, O., Van Der Valk, P., Van Groeningen, C. J., Kuiper, C. M., ... Giaccone, G. (1994). Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. Journal of Clinical Oncology, 12(4), 812-819.

Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. / Linn, Sabine C.; Van Kolken, Coenraad K.; Van Tellingen, Olaf; Van Der Valk, Paul; Van Groeningen, Cornelis J.; Kuiper, Catharina M.; Pinedo, Herbert M.; Giaccone, Giuseppe.

In: Journal of Clinical Oncology, Vol. 12, No. 4, 04.1994, p. 812-819.

Research output: Contribution to journalArticle

Linn, SC, Van Kolken, CK, Van Tellingen, O, Van Der Valk, P, Van Groeningen, CJ, Kuiper, CM, Pinedo, HM & Giaccone, G 1994, 'Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil', Journal of Clinical Oncology, vol. 12, no. 4, pp. 812-819.
Linn SC, Van Kolken CK, Van Tellingen O, Van Der Valk P, Van Groeningen CJ, Kuiper CM et al. Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. Journal of Clinical Oncology. 1994 Apr;12(4):812-819.
Linn, Sabine C. ; Van Kolken, Coenraad K. ; Van Tellingen, Olaf ; Van Der Valk, Paul ; Van Groeningen, Cornelis J. ; Kuiper, Catharina M. ; Pinedo, Herbert M. ; Giaccone, Giuseppe. / Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil. In: Journal of Clinical Oncology. 1994 ; Vol. 12, No. 4. pp. 812-819.
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abstract = "Purpose: To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue. Patients and Methods: Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (IV) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay. Results: The bepridil plasma level was greater than 2 μmol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QT(c)-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone. Conclusion: Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.",
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AU - Van Der Valk, Paul

AU - Van Groeningen, Cornelis J.

AU - Kuiper, Catharina M.

AU - Pinedo, Herbert M.

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N2 - Purpose: To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue. Patients and Methods: Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (IV) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay. Results: The bepridil plasma level was greater than 2 μmol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QT(c)-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone. Conclusion: Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.

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