Normal tissue protection

Phosphorothioates generally protect normal tissues more than tumors. Tumor protection reported in some animal studies can pardy be explained by physiological effects of the particular dmgs, which are specific to rodents (4). WR-2721 does not appear to protect human and most animal tumors, apparentiy because of the low availabiUty of the dmg to tumor cells (4). Many tumors appear to have a reduced capillary density (44), which may mean that these tumors have altered levels of alkaline phosphatase, the enzyme that converts WR-2721 to WR-1065. A reduced abiUty of thiols to protect the hypoxic cells characteristic of many tumors may also contribute to their selectivity for normal tissues. The observation that WR-1065 protects cultured normal human fibroblasts, but not fibrosarcoma tumor cells, suggests that additional factors may contribute to the selectivity of radioprotection by WR-2721 m vivo (18). 

A clinical trial to evaluate misoprostol as a protector of normal tissue during a course of XRT in cancer patients suggests a reduction in acute normal tissue injury (215). A randomized, prospective, double-blind study indicates that topical misoprostol, administered as an oral rinse 15-20 min before irradiation using conventional 2-Gy (200 rad) fractions, five days a week over 6—7 weeks, significantly protects the oral mucosa from radiomucositis, a frequently observed normal tissue complication during XRT for head and neck cancer (215). 

Sensitizer A sensitizer is defined by OSHA as "a chemical that causes a substantial proportion of exposed people or animals to develop an allergic reaction in normal tissue after repeated exposure to the chemical." The condition of being sensitized to a chemical is also called chemical hypersensitivity. Certain chemicals have no immediate health effect. But if you are exposed to them several times, they can make you allergic or sensitive to other chemicals. A classic example is formaldehyde (HCHO). Typical reactions to sensitizers can include skin disorders such as eczema. When working with sensitizers, always use proper protective equipment such as gloves, respirators, etc. Once you are sensitized to a particular chemical, even minute amounts will cause symptoms. Sensitization is usually a lifelong effect. 

Interestingly, the combined supplementation of P-carotene, a-tocopherol, and ascorbic acid has been reported to be protective against 4-(methylnitrosamino)-l-(3-pyridyl)-l-butanone (NNK)-induced lung carcinogenesis in smoke-exposed ferrets through maintaining normal tissue levels... 

Differences in environmental and dietary factors may contribute to the differences in allele frequencies in the African/African American, Caucasian and Asian populations. PGP exists in several normal tissues where it probably has the physiological role of excreting xenobiotics and protecting important tissues from such compounds when they are present in the blood [62, 63]. Allelic differences of sev-... 

As discussed above there are several hurdles to overcome in attempting to enhance the delivery of the drug to the tumour cell. In addition to the use of high dose chemotherapy with concomitant protection of normal tissues, a number of other approaches have been developed. Local perfusion is used with significant benefit in some cancers. This technique is however limited to cancers localized to a single site, e.g. to one of the extremities. This approach will not be discussed here. 

The mechanism by which the more recently used WR-2721 (Fig. 8) reduces nephrotoxicity is not very well understood. WR-2721 protects against nephrotoxicity when administered just prior to cis-Pt (144,145) and it is known that WR-2721 is preferentially taken up by normal cells and not by tumor cells (146). Recently, it was concluded that the uncharged form of the dephosphorylated WR-2721 (known as WE-1065) is the actual species taken up by both normal and tumor cells (147). It has been proposed that the conversion of WR-2721 to WR-1065 is slower in tumors, compared with normal tissues (147), possibly because tumors generally have lower levels of alkaline phosphatase (148). Furthermore, it has been proposed (147) that once formed, WR-1065 will have a decreased uptake rate in tumors, probably as a consequence of their lower pH (149) as compared with normal tissues i.e., the neutral form of WR-1065 will only constitute 0.1% of the total drug present at pH 7 and 1% of the total at pH 8. The reactive WR-1065 is likely to bind directly to cis-Pt, thereby preventing side reactions of cis-Pt. 

As indicated earlier, COX-2 selective drugs may reduce the risk of toxicity to the stomach, kidneys, and other tissues because these drugs spare the production of normal or protective prostaglandins in these tissues.3 These drugs may cause other problems such as diarrhea, heartburn, gastrointestinal cramps, and an increased risk of upper respiratory tract infection. As indicated in Chapter 15, COX-2 drugs have also been associated with serious cardiovascular problems (heart attack, stroke), and these drugs should be avoided in people at risk for cardiac disease. 

Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55-5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide. 

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