Vinorelbine tartrate and paclitaxel combinations: enhanced activity against in vivo P388 murine leukemia cells.
BACKGROUND
Many critical cellular functions such as mitosis, cell movement, and maintenance of cell structure are performed by microtubules. Antimicrotubule agents (which disrupt or block the formation of microtubules) are among the most widely used anticancer drugs and have contributed to the curative therapy of many neoplasms. Recently, two new antimicrotubule agents, vinorelbine tartrate (Navelbine) and paclitaxel (Taxol) have demonstrated clinical activity against ovarian, breast, and non-small-cell lung carcinomas. These agents target microtubules at different sites, and they both interfere with mitotic spindle function. Since vinorelbine tartrate and paclitaxel have shown a similar antitumor profile in clinical trials thus far, it is reasonable to expect that they may be used interchangeably in some combination therapies or perhaps with each other in the same treatment regimen.


OBJECTIVE
On the basis of their similar activity profile in clinical trials, we decided to investigate the therapeutic outcome of a vinorelbine tartrate and paclitaxel binary drug combination, even though they appeared to have overlapping toxic effects. We wanted to ascertain the effect of this binary drug combination, in an in vivo setting, as it related to host toxicity and antitumor activity.


METHODS
CDF-1 female mice that were implanted intraperitoneally with one million P388 murine leukemia cells were treated intraperitoneally with vinorelbine tartrate, paclitaxel, or a combination of the two drugs on a day-1, -5, and -9 dosing schedule. 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 single agents, neither vinorelbine tartrate nor paclitaxel generated meaningful 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 LD10 (dose lethal to 10% of the mice) of vinorelbine tartrate increased approximately 2.5-fold in the presence of paclitaxel and allowed otherwise lethal vinorelbine tartrate doses to be administered safely, which may have contributed to the antitumor efficacy of the combinations. The effect of the time delay between vinorelbine tartrate and paclitaxel administration on toxicity and cures appeared to be contingent on the vinorelbine tartrate dose.


CONCLUSIONS
Results suggest that the overlapping toxic effects of vinorelbine tartrate and paclitaxel might not be a deterrent to their use in combination drug therapy. When used appropriately, rather than having enhanced toxic effects, otherwise toxic doses were better tolerated and survival improved over single-agent therapy.
Knick
V C
VC
Division of Cell Biology, Burroughs Wellcome Co., Research Triangle Park, NC 27709, USA.
Eberwein
D J
DJ
Miller
C G
CG
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D007941:Leukemia P388 / Q000188:drug therapy*; D051379:Mice; D008815:Mice, Inbred Strains; D017239:Paclitaxel / Q000494:pharmacology; D016019:Survival Analysis; D014747:Vinblastine / Q000031:analogs & derivatives / Q000494:pharmacology; D000077235:Vinorelbine
D014747:Vinblastine; D017239:Paclitaxel; D000077235:Vinorelbine