In vitro studies of ways to overcome resistance to VAMP--high dose melphalan in the treatment of multiple myeloma.
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.
Millar
B C
BC
Section of Medicine, Institute of Cancer Research, Sutton, Surrey.
Bell
J B
JB
Maitland
J A
JA
Zuiable
A
A
Gore
M E
ME
Selby
P J
PJ
McElwain
T J
TJ
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002066:Busulfan / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003114:Colony-Forming Units Assay; D003630:Daunorubicin / Q000378:metabolism; D004317:Doxorubicin / Q000627:therapeutic use / Q000633:toxicity; D004351:Drug Resistance; D006801:Humans; D008558:Melphalan / Q000627:therapeutic use* / Q000633:toxicity; D008775:Methylprednisolone / Q000627:therapeutic use; D009101:Multiple Myeloma / Q000188:drug therapy*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D014700:Verapamil / Q000494:pharmacology; D014750:Vincristine / Q000627:therapeutic use
D014750:Vincristine; D004317:Doxorubicin; D014700:Verapamil; D002066:Busulfan; D008558:Melphalan; D008775:Methylprednisolone; D003630:Daunorubicin