Enhancement of Vincristine Cytotoxicity in Drug-Resistant Cells by Simultaneous Treatment With Onconase, an Antitumor Ribonuclease

Susanna M. Rybak, John W. Pearson, William E. Fogler, Kirk Volker, Sally E. Spence, Dianne L. Newton, Stanislaw M. Mikulski, Wojciech Ardelt, Charles W. Riggs, Hsiang-Fu Kung, Dan L. Longo
1996 Journal of the National Cancer Institute  
Onconase, a protein isolated from oocytes and early embryos of the frog Rana pipiens, shares extensive homology with bovine pancreatic ribonuclease (RNase A) and possesses similar enzyme activity. Onconase is cytotoxic toward cancer cells in vitro and exhibits antitumor activity in animal models. In addition, Onconase has been shown to enhance the cytotoxic activity of some chemotherapeutic agents in vitro. Purpose: We studied interactions between the cytotoxic effects of Onconase and the
more » ... herapeutic agent vincristine (VCR) in the treatment of drug-sensitive and multidrug-resistant human colon carcinoma cells in vitro and in mice. Methods: Transplantable human colon carcinoma cells (HT-29 par cells) were infected with a retrovirus containing human mdrl (also known as MDR1 and PGY1) complementary DNA (encoding P-glycoprotein [P-gp]), and clones that were cross-resistant to colchicine, doxorubicin, and vinblastine were selected (HT-29 mdrl cells). Drug-resistant HT-29 mdrl cells and drug-sensitive HT-29 par parental cells were treated with Onconase and/or VCR in vitro at varying concentrations to measure the effects on protein synthesis and cell viability. The impact of Onconase on VCR accumulation in both types of cells was determined in the presence or absence of MRK-16, an anti-P-gp monoclonal antibody capable of reversing the multidrug-resistant
doi:10.1093/jnci/88.11.747 pmid:8637029 fatcat:lmlxnroggfhrxetrygd6t2mpnq