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RESEARCH PRODUCT

Physiological Mechanisms of Treatment Resistance

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It is generally accepted that tumor perfusion, microcirculation, characteristics of the interstitial space of tumors, oxygen (and nutrient) supply, tissue pH distribution and the bioenergetic status—factors that are usually closely linked and that define the so-called pathophysiological microenvironment—can markedly influence the therapeutic response of malignant tumors to sparsely ionizing radiation, chemotherapy, photodynamic therapy, hormonal therapy and immunotherapy. Besides more direct mechanisms involved in the development of acquired therapeutic resistance, there are in addition, obstacles in intratumor pharmacokinetics of antitumor agents due to delivery problems caused by an inadequate and heterogeneous perfusion and barriers within the interstitial compartment. Indirect effects causing therapeutic resistance include lower cell proliferation rates and cell cycle arrest. Changes in transcriptome, alterations in gene expression and in the genome, genomic instability and clonal selection can drive subsequent events that are known to further increase resistance to therapy, in addition to critically affecting longterm prognosis.