Biomarkers of response

Fig. 2. Dynamic steps in the drug development cycle. As explained in the text, multiple strategies can be used for initial drug target discovery, and at various steps in validating the drug target, mechanisms of action, or defining biomarkers of response, new drug targets can emerge.

An earlier cross sectional study had found that the PME/PDE ratio was a measure of disease severity in chronic hepatitis-C. ° More recently, it was found that this ratio may also serve as a biomarker of response to treatment with antiviral therapy. ° Whereas non-responders had similar or even elevated PME/PDE initially, that ratio declined from 0.27 0.02 (standard error) to 0.16 0.01 after treatment (p<0.001) in responders. Liver resection is a common therapy for liver metastases. Prior portal vein embolization (PVE) of the resected lobe results in h) ertrophy of the remaining contralateral lobe. Phosphorus-31 MRSI has been used to monitor metabolism of the regenerating lobe after PVE. ° ... 

There are thus three types of biomarkers biomarkers of exposure of the organism to the toxic substance, biomarkers of response of the organism to that exposure, and biomarkers of susceptibility of the organism to the chemical. 

Biomarkers are used at several stages in the risk assessment process. Biomarkers of exposure are important in risk assessment, as an indication of the internal dose is necessary for the proper description of the dose-response relationship. Similarly, biomarkers of response are necessary for determination of the no observed adverse effect level (NOAEL) and the dose-response relationship (see below). Biomarkers of susceptibility may be important for identifying especially sensitive groups to estimate an uncertainty factor. 

From these mechanistic studies, specific biomarkers of effective exposure were proposed the DNA adducts ethenodeoxyadenosine and ethenodeoxycytidine. These can be detected in liver biopsy and white blood cells and so can be used to monitor workers. Furthermore, more recently, a specific biomarker of response has also been detected. This is a mutant p21 ras protein, which results from the interaction with DNA and can be detected in the serum of workers exposed to vinyl chloride. The level of this protein detected in workers was found to have increased as exposure to vinyl chloride increased. Therefore, both these biomarkers can be used in risk assessment. 

Biomarkers of response, also referred to as biomarkers of effect or disease, measure an event resulting from a toxic interaction, which is predictive of an adverse health effect or is an adverse health effect. The development of biomarkers of effect and their use in studies have many public health applications, including providing information of the etiology of disease, early detection of disease (screening), and evaluating the efficiency of therapeutic agents. Biomarkers of effect also are useful in... 

Dehdashti F, et al. PET-based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor-positive breast cancer. Breast Cancer Res Treat. 2009 113 509-517. 

Sweet, L.I., D.R. Passino-Reader, P.G. Meier and G.M. Omann. Xenobiotic-induced apoptosis significance and potential application as a general biomarker of response. Biomarkers 4 237-253, 1999. 

Discovery of new diagnostic and prognostic indicators and biomarkers of therapeutic response, and prediction of patients most likely to benefit from the diug and use in general pharmacogenomic studies (Fig. 2)... 

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 3.10 Populations That Are Unusually Susceptible. 

The problem of potentiation was discussed earlier (Chapter 2, Section 2.5). Potentiation is often the consequence of interactions at the toxicokinetic level, especially inhibition of detoxication or increased activation. The consequences of such potentiation may be evident not only at the whole animal level but also in enhanced responses of biomarker assays that measure toxicity (Figure 13.3). By contrast, biomarkers of exposure alone are unlikely to give any indication of potentiation at the toxicokinetic level. 

Kreps SE, BanzetN, Christiani DC, Polla BS. 1997. Molecular biomarkers of early responses to environmental stressors — implications for risk assessment and pubhc health. Rev Environ Health 12 261-280. 

The ISO protocol for the biochemical response EROD (ISO 23893-2/AWI) as a recent example of a bioanalytical (biomarker) [49,50] method standardised under ISO for fish needs harmonisation with the other test systems and between the laboratories (users) before implementation. Use of biomarkers (biochemical responses) in multi-arrays for environmental monitoring according to Hansen et al. [50] is complementary to chemical analysis since they can alert for the presence of ecotoxic compounds. Bringing into the WFD, the effect-related approaches concerning bioassays and biomarkers are only relevant in the context of the QN of environmental relevant substances and the good chemical status. But it is rather difficult to transfer the monitored biochemical responses or biomarkers into an operational effect-related standard. They serve as the basis for environmental protection against hazardous substances. In relation to... 

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