Combination Therapy Of Ftis Or Ggtis With Cytotoxic Anticancer Drugs Is More Efficacious Than Monotherapy

Evidence from our research and that of others (46-48) indicated that FTIs' antitumor effect is often cytostatic and reversible. This suggested that combination therapy may be beneficial. Furthermore, there are several reasons why combination therapy with FTIs or GGTIs and other clinically used anticancer drugs with different mechanisms ofaction may prove to be more beneficial than monotherapy. First, because a tumor is made up of a heterogeneous population of cells with different genetic alterations, treatment with more than one agent may avoid resistance of the tumor to a single drug. Second, Ras has been shown to induce resistance to radiation and some cytotoxic agents. Therefore, inhibition ofK-Ras prenylation may sensitize human tumors to cytotoxic agents or radiation (see Chapter 12). On the other hand, treatment with cytotoxic agents may also alter tumor cells such that they become even more sensitive to FTIs or GGTIs. To explore these possibilities we have implanted sc FTI-2148-containing mini-pumps (25 mg/kg/d x 14 d) (in mice bearing A-549 cells as in Fig. 4) 2 d prior to treatment with either gem-citabine (80 mpk [ip] every 4th d, 3 times), or cisplatin (5 mpk [ip] every 4th d, 3 times). Our studies have shown that combination therapy is more efficacious than monotherapy (Fig. 8) (72). Similar results were obtained with taxol (12.5 mpk [ip] every 4th d, 3 times) and

FTI-2148 at a lower dose (12.5 mpk/d x 14 d minipump) (Fig. 8). In all cases the effect was additive rather than synergistic. We have also demonstrated that GGTI-2154 in combination with either gemcitabine, cisplatin, or taxol was more effective than monotherapy (72). More extensive studies where dosing and scheduling are optimized are needed in order to determine the most efficacious protocols for these combination therapy studies.

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