Evaluation of Combination Cancer Chemotherapy

Increasing efforts in combination anti-cancer chemo-therapy highlight the demand of developing reliable methodologies to evaluate drug interactions. However, ambiguities and controversies still exist to date in applying the conventionally used evaluation methods such as the combination index approach. The first focused area in this dissertation is the improvement of the reliability and accuracy in using of the combination index method for drug interaction evaluations. The advantage of using non-linear regression in place of the conventionally used linear regression for the parameter fittings associated with the sigmoidal dose-response relationships was demonstrated in Chapter 2. By converting the combination index method to an equivalent way of predicting the zero-interactive combination effect, the mathematical symbolic manipulations in Chapter 3 challenged the validity of the usage of Loewe Additivity model when the dose-response curves of combined agents are not similar. By further mathematical derivations, a new method, the Uncertainty Envelope method, was suggested to be adopted in such cases. Combinations of paclitaxel and suramin of various concentrations discovered a non-conventional dose-sensitization effect of suramin to paclitaxel and the possible mechanism underlying the antagonistic effect between these two agents was discussed. In Chapter 4, paclitaxel in combination with suramin in histoculture and animal model clearly showed that suramin at low dose (<50 mM in culture medium or plasma) sensitized the effect of paclitaxel whereas it at high dose (>50 mM in culture medium or plasma) antagonized paclitaxel effect. The interplay of cell cycle perturbation of both agents was studied as the mechanism underlying the antagonistic interaction. The reduction of fraction of cells in G2/M phase of cell cycle was also found after high dose suramin treatment in xenograft tumors. This supports the hypothesis that suramin countered the paclitaxel efficacy by getting less cells insulted by paclitaxel in M phase of cell cycle. Suramin population pharmacokinetic and pharmacodynamic study in Chapter 6 showed that the actual tumor suramin concentration after low and high dose administration did maintain at chemo-sensitization and chemo-antagonization concentration levels. The findings in this dissertation can potentially benefit the optimization process of therapeutic regimens between suramin and paclitaxel.