Inducible Repair and the Two Forms of Tumour Hypoxia - Time for a Paradigm Shift

Abstract

Clinical experience shows that there is a therapeutic window between 60 and 70 Gy where many tumours are eradicated, but the function of the adjacent normal tissues is preserved. This implies much more cell kill in the tumour than is acceptable in the normal tissue. An SF2 of 0.5 or lower is needed to account for the eradication of all tumour cells, while an SF2 of 0.8 or higher is needed to explain why these doses are tolerated by normal tissues. No such systematic difference is known between the intrinsic sensitivity of well-oxygenated normal and tumour cells. The presence of radioresistant hypoxic cells in tumours makes it even more difficult to understand the clinical success. However, there is experimental evidence that starved cells lose their repair competence as a result of the depletion of cellular energy charge. MRS studies have shown that low ATP levels are a characteristic feature of solid tumours in rodents and man. In this paper we incorporate the concept of repair incompetence in starving, chronically hypoxic cells. The increased sensitivity of such cells has been derived from an analysis of mammalian cell lines showing inducible repair. It is proportional to the SF2 and highest in resistant cells. The distinction between acutely hypoxic radioresistant cells and chronically hypoxic radiosensitive cells provides the key to the realistic modelling of successful radiotherapy. It also opens new conceptual approaches to radiotherapy. We conclude that it is essential to distinguish between these two kinds of hypoxic cells in predictive assays and models.

Quantifying Transient Hypoxia in Human Tumor Xenografts by Flow Cytometry

“…From a therapy standpoint, the presence and fraction of transiently hypoxic cells in a tumor could conceivably dictate the type of treatment strategy that is used (35). For example, strategies that improve tumor perfusion (36) or that involve repeated low doses of radiation (15) or drugs (16) would be expected to target cells with changing hypoxic status. Ideally, quantification of the intermittently hypoxic content of a tumor could be used to individualize treatments designed to target hypoxic tumor cells.…”

“…This chronic hypoxia has been extensively characterized in both animal and human tumor systems, and its impact on cancer therapy is well understood. However, observations in animal tumors more than two decades ago (14) led to suggestions of a more dynamic form of hypoxia, which has more recently been discussed as a potential factor impacting clinical cancer therapy (6,7,15,16). This transient or intermittent hypoxia is poorly understood, and there are many unanswered questions regarding its presence and potential influence in the treatment of solid tumors.…”

“…Transient hypoxia is thought to occur in tumor cells that are dependent on tumor blood vessels that are subject to partial and/or intermittent decreases in functionality, thereby reducing oxygen (and nutrient) delivery and availability. Importantly, as the oxygenation status of these cells increases or decreases over time, there are concomitant changes in their sensitivity to radiation (15) or chemotherapy (16). Moreover, a portion of transiently hypoxic cells are capable of retaining some proliferative capacity during the temporary reduction (or absence) of oxygen (11) and therefore could potentially proliferate upon reoxygenation of a tumor region.…”

“…infusion in patients [plasma half-lives of 30 minutes (37) and 5.1 hours (46), respectively] may not provide an accurate picture of tumor hypoxia when considered over a period of many hours in rodents or a day or more in patients. Changes in hypoxia over longer time intervals may not be considered important when administering a single dose of therapy but could potentially have a substantial impact on tumor response to multi-fractionated radiotherapy (15) or chemotherapy (16). Changes in tumor hypoxia over time may also affect the regrowth potential of a tumor as formerly hypoxic cells may suddenly find themselves in an environment that is better oxygenated and more favorable for proliferation (6,11).…”

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma

“…A more pronounced radiation resistance of chronically hypoxic tumour cells compared to acutely hypoxic tumour cells would also be compatible with the observations. However, experimental data do indicate the opposite, a less pronounced radiation resistance of chronically hypoxic tumour cells (Denekamp and Dasu, 1999). The inhibitory effect of MMC on repopulation is further substantiated by the observation that recurrent tumours after radiotherapy in combination with MMC grew significantly slower compared to recurrent tumours after radiation treatment alone (Figure 6).…”