Tumor Markers of Carcinogenesis and Carcinogen Exposure

31 May

In addition to the use of markers for the detection, diagnosis, therapeutic efficacy, and prognosis of neoplasms within organisms, markers have also been utilized to monitor both experimental

Table 17.11 Requirements for Biological Markers for the Detection and

Monitoring of Human Neoplastic Disease

1.  Specificity for neoplasia

2.  Specificity for tumor type

3.  Should indicate cancer cells in patient before they are clinically evident

4.  Should indicate extent of tumor burden

5.  Should be a sensitive indicator of success of anticancer treatment

6.  Should signal presence of micrometastatic  lesions

7.  Should indicate recurrence of neoplasia

8.  Should be detectable in blood, urine, and tissues

9.  Simplicity and low cost of test

10.  Assay should be sensitive to detect less than 200 million cells

animals and human populations  for their exposure to a variety of environmental  carcinogens. This general field, when applied to humans, has come to be known as molecular epidemiology. In some publications,  this terminology  has been relatively  global, including not only markers resulting from environmental exposures but also markers of genetic predisposition to neoplasia, some of which were considered in Chapter 5 (Perera, 1996). Some of the markers that have been utilized, as well as an indication of their sensitivity and specificity, may be seen in Table 17.12. The determination of urinary 8-hydroxy-2′-deoxyguanosine is utilized as a biological marker of in vivo oxidative DNA damage (Shigenaga et al., 1989). Metabolites of carcinogens, particularly aflatoxin,  have also been useful in monitoring  exposure  of patients  to this carcinogen  (cf.

Table 17.12 Some Commonly Utilized Molecular Epidemiology Markersa

Key: –, low; +, medium; ++, high; +++, very high. T. Comp., technical complexity;  HPLC, high-pressure  liquid chromatography; GCMS, gas chromatography—mass spectroscopy;  PCR, polymerase chain reaction.

aSensitivity refers to the level of exposure inducing the biomarker  modification  (low sensitivity,  high exposure needed). Specificity attests to the rate of false positives and principally  the ability of the test to indicate the in- volvement of specific carcinogens.

Adapted from Izzotti et al., 1997.

Wogan, 1992). Adducts  of hemoglobin  by several different  chemical  carcinogens,  including aflatoxin and polycyclic hydrocarbons as well as aromatic amine carcinogens in smokers, have also been used as a form of molecular dosimetry to chemical carcinogens in humans (Skipper and Tannenbaum,  1990). Measurement  of the levels of DNA adducts by the techniques  de- scribed by a number of workers includes studies both in experimental  animals and in humans (La and Swenberg, 1996; Poirier and Weston, 1996). Such measurements may be used not only as dosimetry studies of exposure but also studies on the effects of preventive environmental fac- tors on the presence of such adducts in blood cells in vivo (Peluso et al., 2000). Bhatnagar and Talaska (1999) have presented a provocative  model of expected cancer rate, exposure history, and biomarker levels in workers exposed to a specific carcinogen  during this century (Figure 17.16). In the model, one can see the potential “latent” period followed by an increase in risk, which then tapers off after cessation of exposure. Such a model could certainly explain a variety of different exposures, especially in the nineteenth century, to various chemical carcinogens. Re- cently, Bartsch (2000) reviewed studies on biomarkers in cancer etiology and prevention over the last two decades, indicating the potential usefulness of such markers in programs and trials of cancer prevention.

Figure 17.16 A model of expected cancer rate, exposure history, and biomarker levels of workers born in 1935 and beginning work with exposure to a carcinogen at age 18. The biomarker levels shown would be consistent with a steady 8 hours per day, 5 days per week exposure and a biomarker with a 120-day half- life. In this model the risk or cancer rate is based on recent age-specific  lung cancer rates in the United States. Note that the biomarker for exposure is present basically only during the period that the worker is exposed because of the relatively brief half-life. (Adapted from Bhatnagar and Talaska, 1999, with permis- sion of the authors and publisher.)

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