Fig. 4

In Vivo Considerations for Synthetic Lethal Therapeutics. When using two or more therapeutics, it is important to determine the drug combination ratios at which synergy occur (a). This should be done in a panel of cell lines for the indication(s) of interest. Synergism may also be dependent on the timing of the administration of the different therapeutics (b). Another challenge that needs to be addressed is the issue associated with drug penetration into the entire tumour (c). As a result of poorly organized vasculature, concentration gradients will be generated upon treatment and outcomes of synthetic lethal approaches may be limited by the inability to induce sufficient genetic alterations in all cells of the targeted population. Finally, while synthetic lethal approaches are promising, certain populations of the tumour may survive treatment due to intra-tumoural heterogeneity which makes them insensitive to the specific treatment regimen (d)