Rapid activation of MDR1 gene expression in human metastatic sarcoma afterin vivo exposure to doxorubicin

Overexpression of P-glycoprotein (Pgp), a multidrug transporter encoded by the MDR1 gene, is associated with chemoresistance in some human solid tumor malignancies. To date, analyses of MDR1 levels in solid tumors have examin ed constitutive increases in expression at relapse. In the present study, m e have evaluated the acute induction of MDR1 gene expression in a solid hum an tumor as a function of time in response to in vivo exposure to chemother apy, Five patients with unresectable sarcoma pulmonary metastases underwent isolated single lung perfusion with doxorubicin, Relative MDR1 gene expres sion tvas measured in metastatic tumor nodules and normal lung specimens af ter initiation of chemoperfusion. In four of five patients, a 3-15-fold (me dian, 6.8) increase in MDR1 RNA levels was detected in tumors at 50 min aft er administration of doxorubicin, In contrast, normal lung samples had very low levels of MDR1 RNA prior to perfusion, and no acute increases were obs erved after therapy. These findings demonstrate, for the first time, that M DR1 gene expression ran be rapidly activated in human tumors after transien t in vivo exposure to cytotoxic chemotherapy.