Some aspects of size-dependent differential drug response in primary and metastatic tumors

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Abstract
The response of cancer to various anticancer drugs is tumor-size dependent in many aspects. In general, problems stem partly from the fact that the entire tumor cell populations do not respond equally to a certain treatment. As a result of recent progress in cancer biology, it has become evident that cellular heterogeneity of the tumor underlies the difficulties of treating primary and metastatic tumors with chemotherapy. Moreover, as tumors grow, marked diversity develops on the tissue level as well. An uneven distribution with an increase of areas of lower growth fraction and of poorer drug delivery is more distinct in larger tumors. Heterogeneous distribution and low levels of tumor blood flow are considered to be causally related to the heterogeneous nature of tumor tissue. Considering the lack of evidence of a lymphatic system within the tumor, increased interstitial fluid pressure may be a natural result that further impedes blood flow in the tumor. The fact that the temporary and selective increase in tumor tissue blood flow by angiotensin-induced hypertension produces a remarkable chemotherapeutic effect should vividly indicate that delivery of the drug to the tumor is really the ‘bottleneck’ of cancer chemotherapy. Tumor-size-related change in the transvascular and extravascular transport of molecules and its relevance to chemotherapy are also discussed in this article.