Tumor hypoxia: A target for selective cancer therapy

Abstract

Tumor hypoxia has been considered to be a potential therapeutic problem because it renders solid tumors more resistant to sparsely ionizing radiation (IR) and chemotherapeutic drugs. Moreover, recent laboratory and clinical data have shown that tumor hypoxia is also associated with a more malignant phenotype and poor survival in patients suffering from various solid tumors. Therefore, selective targeting of hypoxic tumor cells has been explored, and since severe hypoxia (pO 2 < < < <0.33%, 2.5 mmHg) does not occur in normal tissue, tumor hypoxia could be exploited for therapeutic advantage. However, the following three characteristics of hypoxic tumor regions present obstacles in targeting hypoxic cells. First, it is difficult to deliver a sufficient amount of drug to a region that is remote from blood vessels. Second, one must specifically target hypoxic tumor cells while sparing normal well-oxygenated tissue from damage. Finally, the severely hypoxic tumor cells to be attacked have often stopped dividing. Therefore, high delivery efficiency, high specificity and selective cytotoxicity are all necessary to target and combat hypoxic tumor cells. The current review describes progress on the biological aspects of tumor hypoxia and provides a compilation of the recent molecular approaches used to target hypoxic tumors. These approaches include our work with a unique hypoxia-targeting protein drug, TOP3, with which we have sought to address the above three difficulties. (Cancer Sci 2003; 94: 1021-1028) n solid tumors, oxygen delivery to the respiring neoplastic and stromal cells is frequently reduced or even abolished by deteriorating diffusion geometry, severe structural abnormalities of tumor microvessels, and damaged microcirculation.1) It has been known for some time that tumor cells can survive and even grow in such a deteriorated microenvironment. Moreover, as described in detail below, tumor hypoxia has been shown to be a cause of malignant transformation and a source of resistance to current cancer therapies. For these reasons, approaches to targeting hypoxic tumor cells have been sought over a period of years. Recent progress in understanding the molecular mechanisms of hypoxic response, and especially the discovery of a key molecule, Hypoxia Inducible Factor (HIF), as well as improvements in diagnostic techniques through which the tumor microenvironment can be assessed, has opened the door to a solution of this longstanding issue.

Differential Responses of Myogenic C2C12 Cells to Hypoxia between Growth and Muscle-Induction Phases: Growth, Differentiation and Motility

“…It is also well known that hypoxia enhances the proliferation of cancer cells 45,46) . HIF-1α is one of the key molecules contributing to cancer progression [46][47][48] , making it a target molecule for cancer therapies 47,48) . Induction of HIF-1α protein is required for the growth enhancement hypoxic cells 22,[46][47][48] .…”

“…HIF-1α is one of the key molecules contributing to cancer progression [46][47][48] , making it a target molecule for cancer therapies 47,48) . Induction of HIF-1α protein is required for the growth enhancement hypoxic cells 22,[46][47][48] . In C2C12 cells, HIF-1α protein was induced by myogenic induction in the present study, in agreement with previous reports 26,49) .…”

Hypoxia Stabilizes Microtubule Networks and Decreases Tumor Cell Chemosensitivity to Anticancer Drugs Through Egr‐1

“…Hypoxia is considered to be a potential barrier for treating tumors because it induces the development of cell clones with an aggressive and treatment-resistant phenotype, which leads to rapid progression and poor prognosis (Kizaka-Kondoh et al, 2003;Vaupel, 2008). It has been shown that hypoxia can decrease the therapeutic efficacy of radiation treatment, surgery, and some forms of chemotherapy.…”

Significance of HIF-1-active cells in angiogenesis and radioresistance

“…In order to eradicate HIF-1a-expressing hypoxic cells, we have developed TOP3 (TAT-ODD-procaspase-3), a fusion protein with three domains (Figure 1) (Harada et al, 2002(Harada et al, , 2005(Harada et al, , 2006Kizaka-Kondoh et al, 2003;Inoue et al, 2004). The PTD is derived from the protein-transduction domain (PTD) of the human immunodeficiency virus type-1 tat protein (Schwarze et al, 1999) and efficiently delivers TOP3 to any tissue in vivo.…”