Hypoxic sensitivity

The oxidation of DNA radicals by hypoxic sensitizers, normally nitro compounds, has found considerable interest in the context of attempts to improve irradiation regimes in the radiotherapy of solid tumors (Chap. 12.11). Concomitantly, model studies have been undertaken in order to shed some light on potential mechanism of their reactions. p-Nitroacetophenone (PNAP) has often been used as a convenient model sensitizer. 

Porschen W, Bosiljanoff P, Gewehr K, Muhlensiepen H, Weber HJ, Dietzel F, Feinendegen LE (1977) In vivo assay of the radiation sensitivity of hypoxic tumour cells. Influence of radiation quality and hypoxic sensitization. In Radiobiological research and radiotherapy, Vol. 1. International Atomic Agency, Vienna, pp 181-194... 

The second class of materials that has been the subject of clinical study in the context of XRT sensitization is the so-called hypoxic sensitizers. These agents are electron-affinic compounds that exacerbate damage induced by ionizing radiation... 

As detailed in the context of the hypoxic sensitizer discussion above, the idea that an easy-to-reduce species could function as a radiation sensitizer is not new [113-117]. Indeed, there is considerable precedent for it both in the radiation sensitization literature per se [113-115,118,125-129,132-135,138,139,142] and in classic mechanistic explanations of radiation-induced cytotoxicity [143-145]. However, as has also been made clear in the context of this earlier discourse, this idea has yet to translate into an FDA-approved XRT sensitizing product. However, as noted above, PCI-0120 (3) possesses special features that led to the consideration that it... 

The fetus is living at low PO2 Mount Everest in utero and is at birth suddenly exposed to high PO2. This transition requires a change of setting of oxygen sensitivity. The carotid and aortic bodies are the main peripheral O2 sensors. While the carotid bodies seem to be the main peripheral chemoreceptors involved in respiratory control, the aortic bodies are more involved in cardiovascular homeostasis in the fetus (1). They have a low hypoxic sensitivity and their involvement in the hypoxic ventilatory response is controversial (2). 

Maturation of [Ca +] Responses to CO2 and O2-CO2 Interaction Several studies (in vivo) have shown that the carotid chemoreceptor neural response to CO2 is also weak in the newborn and increases with age (11,14). Therefore, it was proposed that maturation of carotid chemoreceptor hypoxic sensitivity may be related to development of O2-CO2 interaction (74). In an early study of rats 1-14... 

Kumar P, Hanson MA. Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the new-born lamb. J Dev Physiol 1989 11 (4) 199-206. 

Tatsumi K, Pickett CK, Weil JV Decreased carotid body hypoxic sensitivity in chronic hypoxia role of dopamine. Respir Physiol 1995 101(l) 47-57. 

Blanco CE, Dawes GS, Hanson MA, McCooke HB. The response to hypoxia of arterial chemoreceptors in fetal sheep and newborn lambs. J Physiol 1984 351 25-37. Kumar P, Hanson MA. Re-setting of the hypoxic sensitivity of aortic chemoreceptors in the newborn lamb. J Dev Physiol 1989 11 199-206. 

Endogenous NO exerts a tonic inhibitory influence on carotid body activity. Evidence includes (1) NOS inhibitors augment basehne activity and potentiate the sensory response to hypoxia, and (2) NO donors inhibit the sensory activity (see Ref. 67 for references). Furthermore, targeted deletion of the NOS-1 isoform leads to an enhanced peripheral chemoreceptor sensitivity to hypoxia (34) and this is further confirmed by direct measurements of carotid body activity (35). On the other hand, hypoxic sensitivity of the carotid body seems to be depressed in NOS-3-deficient mice (36). It has been suggested that chronic vasoconstriction in NOS-3-deficient mice may render the carotid body insensitive to hypoxia. Reported cellular mecha-... 

Vizek M, Pickett CK, Well JV Increased carotid body hypoxic sensitivity during acclimatization to hypoharic hypoxia. J Appl Physiol 1987 63 2403-2410. 

The functional changes within the carotid bodies are tightly connected to the anatomical and neurochemical changes occurring imder chronic hypoxia. If some results show decreased carotid body hypoxic sensitivity after chronic hypoxia (22), it is now well established that successful ventilatory acclimatization relies on an increased sensitivity of carotid body chemoreceptors. Actually, numerous experimental approaches, ranging from hypoxic ventilatory response in awake animals (10,23) to in vitro measurements of ion channel function on glomic cells (24), are consistent with increased carotid body sensitivity following chronic hypoxia. 

In earher studies (22,23), hypoxic sensitivity was observed in neonatal (Pl-2) but not juvenile (PI3-20) rat AMC, consistent with a loss of the nonneurogenic... 

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