Resistance to Chemotherapy in Cancer: A Complex and Integrated Cellular Response

Abstract

Inherent and acquired resistance pathways account for the high rate of failure in cancer chemotherapy. The mechanisms or pathways mediating resistance may be classified as pharmacokinetic (i.e. alter intratumour drug exposue) or pharmacodynamic (i.e. failure to elicit cytotoxicity). More often than not, the resistant phenotype is characterised by alterations in multiple pathways. Consequently, the pathways may act synergistically or generate a broad spectrum of resistance to anticancer drugs. There has been a great deal of systematic characterisation of drug resistance in vitro. However, translating this greater understanding into clinical efficacy has rarely been achieved. This review explores the phenomenon of drug resistance in cancer and highlights the gap between in vitro and in vivo observations. This gap presents a major obstacle in overcoming drug resistance and restoring sensitivity to chemotherapy.

Expression of the copper transporters hCtr1, ATP7A and ATP7B is associated with the response to chemotherapy and survival time in patients with resected non-small cell lung cancer

“…Molecularly, platinum-resistance is multifaceted (9)(10)(11). One mechanism of resistance is the reduction in the intracellular accumulation of the drug, which occurs due to the impairment of drug intake, enhancement of outward transport or a combination of the two in tumor cells (1).…”

Diagnostic Platform for Personalized Chemosensitivity Assays - Robust Results via Process Automation

“…Thus, relapse rates appear to be high and alternative cytostatic treatment becomes noteworthy. The patient's quality of life is limited and the unknown efficacy of the treatment may result in the patient's death [5,6]. Presently, ex vivo chemosensitivity screening is a proven scientific method [1]: It can verifiably evaluate the efficacy of cytostatic drug combinations [7].…”

Multidrug resistance: overcoming the good, the bad, and the ugly

“…These may involve the activity of different types of drug transporters (including the adenosine triphosphate [ATP]-binding cassette [ABC] family, of which MDR1 is a member). Enzymes causing metabolic inactivation or degradation of drugs, DNA repair enzymes, and proteins that prevent apoptosis are among the multiple other mechanisms [4].…”

“…Since the functions conferring drug resistance are, in many cases, essential for integrity of the cell and survival of the organism, agents that reverse drug resistance can be unduly toxic to normal tissues [4]. These challenging aspects of anticancer treatment are reviewed by Drain et al with regard to lymphoid malignancies [1].…”

“…Furthermore, the situation can become even more complex when the chemotherapy drugs themselves cause the induction of drug resistance. There are many potential genetic mechanisms for this to occur [4]. For example, transporter efflux genes can become up-regulated, activating genes can become down-regulated, and metabolizing genes can become altered to reduce efficacy of treatment.…”