4944

Quantitative determination of synergistic/antagonistic combinations of antitumor agents in vitro in terms of isobologram and combination index (CI) is relatively easy to be carried out using computer simulation. However, drug combination against xenograft tumor is frequently complicated by variability, experimental size, experimental optimization and cost. This paper demonstrates how to overcome these difficulties by using microtubule targeting antitumor agents, Taxotere (TXT) and T900607 (T607), as examples and using the median-effect principle (Chou) and the CI method (Chou-Talalay). We have succeeded in quantitative determination and antitumor synergism of these two drugs without enhancement of toxicity. This conclusion is reached with i) constant ratio combination (diagonal scheme); ii) previously established optimal conditions (doses, schedule and route) and with determining tumor size and body weight changes; and iii) the use of new computer software “CompuSyn” (Chou & Martin, 2003). In all, only 72 nude mice were used and about 2 months were spent for each experiment. Human colon carcinoma HCT-116 xenografts were implanted on day 0, and i.v. treatment, Q3Dx4 and x3 were started on day 14 with TXT (3, 5, 6, 7 mg/kg) and/or T607 (15, 25, 30, 35mg/kg) on day 14, 17, 20, 23, 32, 35 and 38, (n=6). Computerized analysis indicates that synergism (CI<1) occurred on day 32 with increasing synergism on D35 as indicated by the Fa-CI plots and the isobologram. Surprisingly, body weight decreases during and after combination treatment were less than those treated with each drug alone. This is considered a rare incidence of mutual protection in toxicity. Computer simulation of dose-reduction index (DRI) indicates that TXT doses can be reduced by 1.8-fold and T607 doses can be reduced by 4.5-fold when compared with each drug alone for a given degree of tumor suppression. Thus, decreases in dose led to decrease in toxicity while not compromising therapeutic effects. In a similar experiment with human mammary carcinoma MX-1 xenografts, T607 (25-35mg/kg) and TXT (7.5-15mg/kg) Q3Dx4, i.v. were given on D7, 10, 13 and 16. Increasing therapeutic synergism was observed on 16, 19 and 21. On D19, T607 (30mg/kg) and TXT (15mg/kg) resulted in 0/6 and 2/4 tumor disappearance, respectively, whereas in combination 5/5 tumor disappearance was observed. These results suggest that in vivo drug combinations can be conducted efficiently and synergy can be quantitatively determined, and that combination of TXT and T-607 for clinical development is warranted.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]