Tumor hypoxia: its impact on cancer therapy

Abstract

The presence of radiation resistant cells in solid human tumors is believed to be a major reason why radiotherapy fails to eradicate some such neoplasms. The presence of unperfused regions containing hypoxic cells may also contribute to resistance to some chemotherapeutic agents. This paper reviews the evidence that radiation resistant hypoxic cells exist in solid tumors, the assumptions and results of the methods used to detect hypoxic cells, and the causes and nature of tumor hypoxia. Evidence that radiation resistant hypoxic cells exist in the vast majority of transplanted rodent tumors and xenografted human tumors is direct and convincing, but problems with the current methodology make quantitative statements about the magnitude of the hypoxic fractions problematic. Evidence that radiation resistant hypoxic cells exist in human tumors is considerably more indirect than the evidence for their existence in transplanted tumors, but it is convincing. However, evidence that hypoxic cells are a significant cause of local failure after optimal clinical radiotherapy or chemotherapy regimens is limited and less definitive. The nature and causes of tumor hypoxia are not definitively known. In particular, it is not certain whether hypoxia is a chronic or a transient state, whether hypoxic cells are proliferating or quiescent, or whether hypoxic cells have the same repair capacity as aerobic cells. A number of new methods for assessing hypoxia are reviewed. While there are still problems with all of the new techniques, some of them have the potential of allowing the assessment of hypoxia in individual human tumors.

Overexpression of hypoxia-inducible-factor 1α(HIF-1α) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage

“…Hypoxia has been shown to compromise the beneficial effects of chemotherapeutic drugs (Teicher, 1994) and interfere with the response of tumours to radiation (Moulder and Rockwell, 1987). Pretreatment oxygenation levels have been found to be predictive of the radiation response and survival of patients with cancer of the uterine cervix (Hockel et al, 1993;Fyles et al, 1998), head and neck (Gatenby et al, 1988;Nordsmark et al, 1996), oropharyngeal (Aebersold et al, 2001), and early oesophageal cancer (Koukourakis et al, 2001).…”

Functionality of hypoxia-induced BAX expression in a human glioblastoma xenograft model

“…7 Since the efficacy of radiation therapy hinges on the ability of surrounding normal tissue to tolerate doses of radiation that are cytotoxic to cancer cells, the presence of hypoxic cancer cells severely limits the utility of radiation treatment. 8 Other studies have demonstrated that hypoxic cancer cells are more resistant to chemotherapy than their oxic counterparts. 9,10 The simplest explanation for this phenomenon is distance-cells furthest from blood vessels tend to be exposed to lower drug concentrations.…”

SR 4233 (Tirapazamine): a new anticancer drug exploiting hypoxia in solid tumours

“…One such difference is that a large proportion of solid tumours contain cells at lower levels of oxygenation than occurs in normal tissues. Such hypoxia in tumours is found in the vast majority of transplanted rodent tumours (Moulder & Rockwell, 1987) and in human tumours xenografts in immunodeficient mice (Rockwell & Moulder, 1990). There is also compelling evidence from a variety of techniques that hypoxic cells are also present in human solid tumours Mueller-Klieser et al, 1981;Vaupel et al, 1991).…”