Treatment of multidrug resistant (MDR1) murine leukemia with P-glycoprotein substrates accelerates the course of the disease.
The prognosis of patients with tumors expressing P-glycoprotein (P-gp), the MDR1 gene product, is generally poor. It is assumed that this is due to decreased tumor responsiveness that results from decreased drug accumulation. We observed that treatment of animals bearing MDR1-transfected leukemic cells with P-gp substrates (i.e., drugs that are transported by P-gp) significantly worsened host survival compared to treatment with vehicle or non-P-gp substrates. This effect was seen with cancer chemotherapeutic agents (paclitaxel and vincristine) and with the MDR modulator, trans-flupenthixol. To determine the mechanism(s) underlying this observation, we studied alterations in pharmacokinetics, pharmacodynamics, and metastasis. We found that the drug-induced acceleration of disease was associated with increased metastases. P-gp(+) cells treated with P-gp substrates demonstrated several pro-metastatic features, including membrane ruffling and invasion through a hepatocyte monolayer. These results suggest that the treatment of MDR tumors with P-gp substrates may produce changes in malignant behavior that could adversely affect therapeutic outcomes.
Yang
J M
JM
The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA. jyang@rwja.umdnj.edu
Yang
G Y
GY
Medina
D J
DJ
Vassil
A D
AD
Liao
J
J
Hait
W N
WN
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D005475:Flupenthixol / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007941:Leukemia P388 / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology / Q000556:secondary; D008466:Mechlorethamine / Q000494:pharmacology; D051379:Mice; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000493:pharmacokinetics / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008466:Mechlorethamine; D014750:Vincristine; D005475:Flupenthixol; D017239:Paclitaxel