Natural and Acquired Resistance to Cancer Therapies

Inadequate Drug Dose

In addition to cellular mechanisms of drug resistance, pharmacologic and physiologic factors may play a role in outcomes of cancer therapy. Pharmacologic factors include inadequate drug dosing or suboptimal scheduling of agents. Traditionally, cytotoxic drugs have been administered at the maximum tolerated doses based on toxicities to normal tissues. Increased therapeutic efficacies with increasing doses, up to maximum levels of acceptable toxicity, have been demonstrated for virtually all cytotoxins in preclinical models and are supported by clinical data relating dose to efficacy in many cancers.

For recently developed targeted drugs, such as kinase inhibitors, the optimal dose may not be the maximum tolerated dose in patients. The relationships among antitumor efficacy, side effects, pharmacodynamic endpoints, and dose of these agents are complex and require novel methodologies and study designs.

Suboptimal Schedule of Drug Administration

With regard to schedule, drugs with short half-lives and cell cycle phase–specific mechanisms of action are typically more active with continuous drug exposure schedules, such as repeated dosing and continuous infusions. Examples include the antimetabolites cytarabine and 5-fluorouracil, the antibiotic bleomycin, and topoisomerase I inhibitors.

Drug Sanctuary Sites (Central Nervous System and Testis)

A physiologic cause for drug resistance is inadequate distribution of drugs to the central nervous system (CNS) and testis, because of the blood-brain and blood-testicular barriers. A major component of these barriers is endothelial cell expression of the multidrug transporter P-glycoprotein. Thus, relapse in the CNS and testis became evident as major sites of treatment failure after most children with acute lymphoblastic leukemia achieved a clinical complete remission. New treatment strategies such as high-dose methotrexate and intrathecal administration of chemotherapy were devised to circumvent the problem of relapse in these so-called sanctuary sites.

Poor Drug Diffusion into Cancer Tissues

The physiology of abnormal new blood vessel formation (angiogenesis) and areas of poor blood supply may also limit the ability of anticancer drugs to distribute into cancer tissues and thus result in treatment failure. Inhibitors of tumor angiogenesis such as sunitinib and bevacizumab have been shown to normalize tumor vasculature, thus increasing perfusion and distribution of chemotherapeutic drugs and potentially enhancing therapeutic efficacy.