In vitro studies of ways to overcome resistance to VAMP--high dose melphalan in the treatment of multiple myeloma

Br J Haematol. 1989 Feb;71(2):213-22. doi: 10.1111/j.1365-2141.1989.tb04257.x.

Abstract

Myeloma colonies (MY-CFUc) from 7/24 patients undergoing treatment with VAMP (vincristine, adriamycin and methyl prednisolone) and high dose melphalan (HDM) were melphalan-resistant. It was not possible to conclude that VAMP induced melphalan resistance in MY-CFUc, but that resistance is endogenous in some myeloma cell populations. In 12/13 of the same patients of whom four had MY-CFUc which were melphalan resistant, the sensitivity of MY-CFUc and GM-CFUc to busulphan was similar. Thus resistance of MY-CFUc to melphalan did not confer resistance to busulphan. MY-CFUc from 1/7 of a second group of patients were adriamycin-resistant. This resistance was removed when the cells were treated with a combination of verapamil (3 micrograms/ml) and adriamycin. Verapamil also enhanced the toxicity of adriamycin to MY-CFUc from two patients where there was no evidence for adriamycin resistance. In these three patients the sensitivity of both MY-CFUc and GM-CFUc was similar after treatment with verapamil. Verapamil did not affect the uptake or efflux of 3H-daunorubicin in sensitive and resistant RPMI-8226 cells (myeloma) and peripheral blood mononuclear cells from a normal donor; neither did it affect the binding of 3H-daunorubicin to nucleic acid. It is concluded that verapamil may be a useful adjuvant to VAMP chemotherapy and that busulphan may provide an alternative to melphalan in patients whose myeloma cells are melphalan resistant.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Busulfan / toxicity
  • Cell Survival / drug effects
  • Colony-Forming Units Assay
  • Daunorubicin / metabolism
  • Doxorubicin / therapeutic use
  • Doxorubicin / toxicity
  • Drug Resistance
  • Humans
  • Melphalan / therapeutic use*
  • Melphalan / toxicity
  • Methylprednisolone / therapeutic use
  • Multiple Myeloma / drug therapy*
  • Tumor Cells, Cultured / drug effects
  • Tumor Stem Cell Assay
  • Verapamil / pharmacology
  • Vincristine / therapeutic use

Substances

  • Vincristine
  • Doxorubicin
  • Verapamil
  • Busulfan
  • Melphalan
  • Methylprednisolone
  • Daunorubicin

Supplementary concepts

  • VAMP-ME protocol