Mechanisms of Drug Resistance in Cancer Chemotherapy

Abstract

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of response to drug-induced tumour growth inhibition; it may be inherent in a subpopulation of heterogeneous cancer cells or be acquired as a cellular response to drug exposure. Resistance varies. Although regulatory approval may require efficacy in as few as 20% of trial cohorts, a drug may subsequently be used in unselected patients displaying resistance to the treatment. Principal mechanisms may include altered membrane transport involving the P-glycoprotein product of the multidrug resistance (MDR) gene as well as other associated proteins, altered target enzyme (e.g. mutated topoisomerase II), decreased drug activation, increased drug degradation due to altered expression of drug-metabolising enzymes, drug inactivation due to conjugation with increased glutathione, subcellular redistribution, drug interaction, enhanced DNA repair and failure to apoptose as a result of mutated cell cycle proteins such as p53. Attempts to overcome resistance mainly involve the use of combination drug therapy using different classes of drugs with minimally overlapping toxicities to allow maximal dosages and with narrowest cycle intervals, necessary for bone marrow recovery. Adjuvant therapy with P-glycoprotein inhibitors and, in specific instances, the use of growth factor and protein kinase C inhibitors are newer experimental approaches that may also prove effective in abrogating or delaying onset of resistance. Gene knockout using antisense molecules may be another effective way of blocking drug resistance genes. Conversely, drug resistance may also be used to good purpose by transplanting retrovirally transformed CD34 cells expressing the MDR gene to protect the bone marrow during high-dose chemotherapy.

Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines

“…MDR is an overall phenomenon resulting from cross-resistance to a variety of structurally and functionally unrelated natural products such as anthracyclines, Vinca alkaloids, epipodophyllotoxins and taxanes. Chemotherapeutic agents such as doxorubicin can select for mutations leading to increased expression of Cytotoxicity and reversal of multidrug resistance by tryptanthrin-derived indoloquinazolines P-glycoprotein and the phenotype of MDR in tissue culture models [9] . Development of adjuvant agents to overcome multidrug resistance (MDR) becomes a new trend in cancer chemotherapy.…”

Molecular mechanisms of drug resistance and its reversal in cancer

“…During anti-estrogen (e.g. tamoxifen) therapy of breast cancer, patients become resistant to endocrine therapy due to obvious loss of estrogen receptors in the resistant tumor cells that were believed not to be dependent on estrogen anymore for their growth (Luqmani, 2005). Sometimes, resistant cancer cells produce a mutated drug target that retains its activity in the cell without being a target of that drug.…”

Resistência de células de carcinoma epidermóide bucal à terapia fotodinâmica mediada pelo ácido 5-aminolevulínico

“…Uma das formas mais significantes de resistência a quimioterápicos é a ação de proteínas de membranas, especialmente transportadores de cassete de ligação de ATP (proteínas ABC), que expulsam a droga do ambiente intracelular e modulam sua distribuição e absorção, mantendo a concentração intracelular abaixo do limiar que induz a morte celular (Luqmani, 2005).…”