Table 1. Issues that may potentially compromise the effectiveness of combination therapy of cancer.

Issue	Description	Example
Limited solubility	One of the drugs is poorly soluble and requires drastic measures to dissolve, compromising the therapy	Paclitaxel has limited solubility and requires high surfactant concentration to solubilize the drug, increasing the risk of adverse drug effects
Limited permeation	One of the drugs has limited ability to permeate across cell membranes, so not all drugs of the combination can achieve sufficiently high intracellular levels	In a combination of chemotherapy drugs with nucleic acid therapy, the nucleic acid molecules can efficiently reach the cytoplasm
Inadequate tumor delivery	In a combination, the drugs that have high molecular weights and have high protein binding affinities tend to penetrate poorly into a solid tumor	DOX does not penetrate far in a tightly packed epithelial tumor, leading to suboptimal DOX levels in portions of tumor
Uneven drug distribution in tumor	Cells in the same tumor are not exposed to all drugs of a combination at their therapeutic levels	For a combination of chemotherapy drugs and chemosensitizer, some cells are not adequately sensitized so they are not fully responsive to the chemo components
Different drug stabilities	One or more of the therapeutic agents in a combination degrade much faster than the other drug(s)	RNA and peptide agents tend to have short in vivo half-lives when compared to many lipophilic chemotherapy drugs, so may need to dose the different components at different frequencies
Different drug half- lives and tumor accumulation	One or more of the therapeutic agents in a combination is eliminated much faster than the other drug(s)	DOX has an elimination half-life 7-10 h, while MMC 15-40 min; MMC accumulates more in tumor at short times, while disappears at 24 h
Alteration of pharmacokinetics and/or metabolism	The component drugs share the same metabolic enzymes and/or elimination pathways	P-gp inhibitors (e.g. valsodar, Elacridar) intended to reverse P-gp-mediated drug resistance could reduce anticancer drugs (e.g. DOX, paclitaxel, vincristine) elimination through the liver or kidneys
Overlapping mechanisms	In a combination, two or more drugs target the same molecular pathways, leading to sub- optimal therapeutic effect and triggering chemoresistance	Use of two taxanes (e.g. paclitaxel and docetaxel) or two anthracyclines (e.g. DOX and daunorubicin)
Overlapping toxicities	In a combination, two or more drugs share similar tissue/ organ toxicity profiles, thus amplifying the adverse drug effects and making it difficult to use near-maximal doses	Overlapping toxicity profiles of bolus 5- FU and irinotecan, which both result in high rates of severe diarrhea
Poor timing or sub- optimal sequence	Some combinations work better with all of the drugs administered simultaneously while some work more optimally if one of the drugs is administered earlier	Apoptotic agent paclitaxel may not help other drugs to penetrate a solid tumor if given together or less than 24 h before other drugs