Cancer Tutorial: Introduction to Drug Resistance

Although the development of new drugs and new drug combinations has resulted in more effective treatment of cancer, a major factor limiting their usefulness is the presence of drug-resistant cancer cells that can exist prior to (intrinsic or de novo drug resistnace) or arise during cancer therapy (acquired drug resistance). Whether drug resistance is intrinsic or acquired, mechanisms conferring altered drug sensitivity may be categorized as invloving a pre-target event, a drug-target interaction, or a post-target event. Mechanisms of drug resistance that result in a modification to the drug itself are called pre-target events because the cellular insult occurs before the drug reaches its intended molecular target. Drug metabolism is one example of a pre-target event because the drug becomes modified before reaching its intended molecular target. Modifications to the drug's intended target, however, can also occur and results in altered drug-target interactions. For example, sequestration of the drug's intended target into a cellular compartment different from the drug can result in the inability of the drug to interact with its target. In other instances, neither the drug nor the drug's target is modfied. Post-target events occur after the drug-target interaction occurs, and thus do not directly involve the drug or the drug's target. For example, altered cell-cycle progression can be a post target event, if the drug's target is not a cell-cycle regulatory protein. However, mechanisms of drug resistance are not mutually exclusive events and thus, there is a fair amount of overlap between the types of drug resistance mechanisms.

Cancer cells have multiple different ways to evade the cytotoxic effects of chemotherapeutic agents. Tumor cells with de novo resistance fail to respond to initial drug treatment. In contrast, tumor cells with acquired drug resistance are initially sensitive to drug exposure, but then become resistant with future drug exposures. The clinical activity of chemotherapy is also dependent on hepatic drug metabolism, extacellular drug concentration, intracellular drug transport, and ability of the drug to access the cancer cells. Furthermore, antitumor agents differ in their ability to diffuse through different tissues. For example, scar tissue from surgery or radiotherapy reduces response rates with chemotherapy, especially in head and neck cancers (Rooney et al., 1985). Also, some tumors can be poorly vascularized and some drugs are unable to cross the blood brain barrier. Therefore, various in vivo factors can influence how much active drug reaqches the molecular target within cancer cells. Cellular drug resistance in humans is complex and appears to be both multifactorial and variable amongst individual patients.


References:

Rooney M, Kish J, Jacobs J, Kinzie J, Weaver A, Crissman J, Al-Sarraf M.
Cancer. 1985 Mar 1;55(5):1123-8

Baguley BC.
Methods Mol Biol. 2010;596:1-14. Review.

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