High frequency of double drug resistance in the B16 melanoma cell line.
Methotrexate (MTX) and N-(phosphonacetyl)-L-aspartate (PALA) are two agents to which cellular resistance can be conferred by gene amplification, but they do not generally show cross resistance. However, combined treatment with these two agents produced drug resistant cells in the B16 melanoma cell line at a much higher frequency than would be expected if resistance to the two agents was totally independent. An isolated doubly resistant clone, B16-F1 MP, showed a high frequency of resistance to pyrazofurin and ouabain, which are also agents to which resistance can be conferred by gene amplification. Thus MTX combined with PALA selected cells with an 'amplificator' phenotype (an increased ability to amplify parts of the genome). These B16-F1 MP cells had a decreased ability to form experimental lung metastases compared with the parent line but this difference was not found in baby hamster kidney cells with the amplificator phenotype. The mechanism underlying drug resistance may need to be considered when designing combination chemotherapy.
McMillan
T J
TJ
Radiotherapy Research Unit, Institute of Cancer Research, Sutton, Surrey U.K.
Kalebic
T
T
Stark
G R
GR
Hart
I R
IR
D000577:Amides; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002460:Cell Line; D003114:Colony-Forming Units Assay; D004351:Drug Resistance / Q000235:genetics; D004357:Drug Synergism; D005784:Gene Amplification; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics; D008727:Methotrexate / Q000627:therapeutic use*; D051379:Mice; D010042:Ouabain / Q000627:therapeutic use; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D011720:Pyrazoles; D012263:Ribonucleosides / Q000627:therapeutic use; D012266:Ribose
D000577:Amides; D000970:Antineoplastic Agents; D011720:Pyrazoles; D012263:Ribonucleosides; D001224:Aspartic Acid; C002997:pyrazofurin; D010042:Ouabain; D012266:Ribose; C013195:sparfosic acid; D010746:Phosphonoacetic Acid; D008727:Methotrexate