Phul, Parvinder Singh; (2006) A study on the predictability of the combined effects of mixtures of anticancer drugs. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Advances in the treatment of cancer have lead to increased survival in many tumour patients. Although the use of combination chemotherapy has become an effective means of improving cancer treatment, methods to predict their combined effects systematically are not in widespread use. This study has looked at seven anticancer drugs with a variety of sites of action. These drugs were tested for their cytotoxicity in DU145 and MCF-7 cancer cells, and a mixture prepared of all seven agents combined at a mixture ratio proportional to their potency. Combined effects of this mixture were predicted using dose response curves for each component using the concepts of independent action and concentration addition. The expectation was that a mixture composed of dissimilarly acting agents should follow the independent action prediction. Instead we observed that this prediction model overestimated the combined effect and that the concentration addition prediction was found to be more accurate. A possible explanation for this phenomenon may be that although these agents display initial dissimilar sites of action, they may have similarity in their methods of promoting tumour cell death. Further study was undertaken to search for how these drugs signal for apoptosis. The cells were treated with each agent and mixture, and analysis for induction of apoptosis showed that each single agent and mixture induced increased apoptosis. Expression of the signalling proteins, p53, caspase-3 and caspase-9 were investigated for both cell lines, although expression of one protein or other was found, a common expression was not found for each drug treatment. The aspect of delivering a potentially effective combination of drugs to the tumour site was also explored and a comparison of the toxicity of a free combination of agents with a combination of agents entrapped in a liposome showed no significant difference.

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