In vivo expression of P-glycoprotein in a human colon carcinoma xenograft is modulated by therapy with free and monoclonal antibody-conjugated vinca alkaloids.
Well established UCLA-P3 human lung tumor xenografts were significantly regressed by treatment with a monoclonal antibody-vinca immunoconjugate whereas no regressions were observed for the LS174T and SW948 human colon carcinoma xenografts by this therapy. Antibody and complementary DNA probes utilized for detection of the MDR1 gene product and mRNA levels, respectively, revealed that prior to drug treatment the lung tumor had virtually no detectable P-glycoprotein while both colon carcinomas displayed low and heterogeneous expression of this resistance-related protein. It was subsequently determined, however, that the low level of P-glyocoprotein expression observed for one of the colon tumors could be rapidly modulated following therapy with free or MoAb-conjugated vinca. These data indicated that elevated P-glycoprotein levels resulting from drug therapy may play a role in the lack of regression of the human colon xenografts. Most significantly, our results also indicated that the time interval between drug treatment and tissue sampling may be a critical factor to be considered in studies which attempt to correlate P-glycoprotein expression with chemotherapy.
Hilselberger Kanitz
M
M
Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, IN 46285.
Mastro
J M
JM
Moore
R E
RE
Starling
J J
JJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D003110:Colonic Neoplasms / Q000737:chemistry / Q000188:drug therapy*; D004351:Drug Resistance; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics; D051379:Mice; D009363:Neoplasm Proteins / Q000032:analysis*; D009368:Neoplasm Transplantation; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D014183:Transplantation, Heterologous; D014747:Vinblastine / Q000031:analogs & derivatives* / Q000627:therapeutic use
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D012333:RNA, Messenger; C055170:4-desacetylvinblastine hydrazide; D014747:Vinblastine