VINORELBINE TARTRATE AND PACLITAXEL COMBINATIONS - ENHANCED ACTIVITY AGAINST IN-VIVO P388 MURINE LEUKEMIA-CELLS

Background: Many critical cellular functions such as mitosis, cell mov ement, and maintenance of cell structure are performed by microtubules , Antimicrotubule agents (which disrupt or block the formation of micr otubules) are among the most widely used anticancer drugs and have con tributed to the curative therapy of many neoplasms, Recently, two new antimicrotubule agents, vinorelbine tartrate (Navelbine) and paclitaxe l (Taxol) have demonstrated clinical activity against ovarian, breast, and nonsmall-cell lung carcinomas, These agents target microtubules a t different sites, and they both interfere with mitotic spindle functi on, Since vinorelbine tartrate and paclitaxel have shown a similar ant itumor profile in clinical trials thus far, it is reasonable to expect that they may be used interchangeably in some combination therapies o r perhaps with each other in the same treatment regimen, Purpose: On t he basis of their similar activity profile in clinical trials, we deci ded to investigate the therapeutic outcome of a vinorelbine tartrate a nd paclitaxel binary drug combination, even though they appeared to ha ve overlapping toxic effects, We wanted to ascertain the effect of thi s binary drug combination, in an in vivo setting, as it related to hos t toxicity and antitumor activity, Methods: CDF-1 female mice that wer e implanted intraperitoneally with one million P388 murine leukemia ce lls were treated intraperitoneally with vinorelbine tartrate, paclitax el, or a combination of the two drugs on a day-1, -5, and -9 dosing sc hedule, Experimental groups had between five and eight mice per group, Vinorelbine tartrate was administered at either 8, 12, 16, 20, or 24 mg/kg and paclitaxel at either 4.5, 18, or 36 mg/kg, Results: As singl e agents, neither vinorelbine tartrate nor paclitaxel generated meanin gful numbers of 60-day cures (i,e,, tumor free at day 60), In contrast , optimal combination regimens produced 60-day cures in more than 80% of the mice. The LD(10) (dose lethal to 10% of the mice) of vinorelbin e tartrate increased approximately 2.5-fold in the presence of paclita xel and otherwise lethal vinorelbine doses to be administered safely, which may have contributed to the antitumor efficacy of the combinatio ns, The effect of the time delay between vinorelbine tartrate and pacl itaxel administration on toxicity and cures appeared to be contingent on the vinorelbine tartrate dose, Conclusions: Results suggest that th e overlapping toxic effects of vinorelbine tartrate and paclitaxel mig ht not be a deterrent to their use in combination drug therapy, When u sed appropriately, rather than having enhanced toxic effects, otherwis e toxic doses were better tolerated and survival improved over single- agent therapy.