Sarcoma Cells Doxorubicin, and Vinblastine in Multidrug Resistant Human Reversal by Cefoperazone of Resistance to Etoposide,

The cephalosporins are a family of semisynthetic antibiotics, some of which have structural features associated with substrates for the multidrug transporter, P-glycoprotein. The activity of a series of six cephalosporins in reversing multidrug resistance (MDK) was examined in MDK variants (Do cells) of the human sarcoma line MES-SA. DxS cells express high levels of the mdr\ gene product P-glycoprotein and are 25to 30-fold resistant to doxorubicin (DOX), etoposide (VP-16), and vinblastine (VBL). Cytotoxicity was measured by the M'lT assay. Cefoperazone (1.0 HIM) was the most effective modulator of MDK, lowering the IC«for VP-16 by 29-fold (29x), for VBL by 16x, and for DOX by 14x. Ceftriaxone at 1.0 HIMproduced lOx modulation of VP-16 cytotoxicity, 8x for DOX, and 2x for VBL. The reversal of resistance was concentration dependent, decreasing to 4x and 5x, respectively, for DOX with 0.25 HIMcefopcra/.one and ceftriaxone. No modulation of cytotoxicity was observed in the parental MES-SA cells, which do not express mdr\. Cefazolin, cefotetan, ccphradine, and ceftazidime were ineffective, producing less than 5x modulation of DOX at 1.0 HIM.Among these cephalosporins, cefopcra/.one and ceftriaxone were the most highly protein bound in the media (30 and 52%), and the most lipid soluble, with octanol/water partitioning coefficients of —¿ 0.49 and —¿ 0.60. Varying the serum concentration in medium from 5 to 50% had less than a two fold effect on the modulation of MDK by ceftriaxone. The ability to reverse MDK among these agents is associated with lipid solubility, high protein binding, a polycyclic planar geometry, and the presence of the piperà /ine group in ccfoperazone. These data and the potential for achieving high tissue concentrations indicate that Cefoperazone merits further study as a modulator of MDR.