Antineoplastic resistance

Antineoplastic resistance, often used interchangeably with chemotherapy resistance, is the multiple drug resistance of neoplastic (cancerous) cells, or the ability of cancer cells to survive and grow despite anti-cancer therapies.

There are two general causes of antineoplastic therapy failure: Inherent properties, such as genetic characteristics, giving cancer cells their resistance, which is rooted in the concept of cancer cell heterogeneity and acquired resistance after drug exposure. Cancer cells can become resistant to multiple drugs by various mechanisms, including: Altered membrane transport, enhanced DNA repair, apoptotic pathway defects, alteration of target molecules, protein and pathway mechanisms, such as enzymatic deactivation. Since cancer is a genetic disease, two genomic events underlie these mechanisms of acquired drug resistance: Genome alterations (e.g. gene amplification and deletion) and epigenetic modifications. Cancer cells are constantly using a variety of tools, involving genes, proteins and altered pathways, to ensure their survival against antineoplastic drugs. This list of mechanism is in no way exhaustive. New and existing ideas of drug resistance mechanisms are being explored and studied, as well as the complex and challenging ways in overcoming such treatment resistance.

Cancer cell heterogeneity, or tumour heterogeneity, is the idea that tumours are made up of different populations of cancer cells that are morphologically, phenotypically and functionally different. Certain populations of cancer cells may possess inherent characteristics, such as genetic mutations and/or epigenetic changes, that confer drug resistance. Administration of antineoplastic drugs kills non-resistant sub-populations and favors those resistant cancer cells. While the tumour mass may shrink as an initial response to the drug, resistant colonies will survive treatment, be selected and then propagate, eventually causing a cancer relapse.

A slightly different way in which cancer cell heterogeneity can give rise to disease progression is via targeted therapy, a type of treatment that targets a specific molecular marker. Tumour cells that do not express the specific marker are not killed, and are then able to divide and mutate further, creating a new heterogeneous tumour, which complicates antineoplastic treatment.

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