The Search for Cancer Diagnostic Markers: A Race Against Time - The knowledge that early detection and treatment offers the best outcome for the patient has long driven the search for effective diagno

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The Search for Cancer Diagnostic Markers: A Race Against Time
The knowledge that early detection and treatment offers the best outcome for the patient has long driven the search for effective diagnostics.


BioPharm International



Table 2. Site-Specific Diagnostic Tests for Cancer
Ovarian cancer is another area that exemplifies the difficulties and pitfalls of establishing accurate and sensitive diagnostic markers. One of the most common causes of cancer-related deaths in women, this disease claimed 13,900 lives in 2001. Because of the difficulty of diagnosing this disorder, Cathro and Stolar11 have examined several markers including calretinin, inhibitin, and the Wilm's tumor gene. They found that in a group of 111 primary ovarian tumors, none of the antigens served to unambiguously distinguish normal from diseased tissue. For example in ovarian sex cord stromal tumors, calretinin detected 76 percent of tumors similar to those identified by inhibitin. Moreover, these markers were evaluated by immunohistochemistry and may be satisfactory for a serum-based test.

Another marker of ovarian cancer is bikunin, a glycoprotein that mediates suppression of metastasis in cancer cells.12 Higher levels of expression in ovarian cancer cells are correlated with lower levels of invasiveness, apparently by downregulating the plasminogen activator and its receptor. Bikunin is produced in the liver, and the authors surmise that different individuals respond with differing levels of synthetic capacity. This would be reflected in the level of suppression of tumor invasiveness. While there is a marked and statistically significant difference in mean serum levels in patients with aggressive disease as compared to disease-free controls and patients with indolent disease, the standard deviation is quite large. Thus while bikunin levels may eventually have predictive value for disease outcome, it is unlikely that this marker will be of value in immunodiagnostic screening programs.

In addition to PSA there is only one FDA-approved test for a cancer related antigen, nuclear matrix protein 22 (NMP22). This is a lateral flow enzyme immunoassay cleared for general screening of urine. However, pyuria and hematuria significantly interfere with the test, and its overall sensitivity was only 66 percent. Numerous other biomarkers have been identified for bladder cancer and are under investigation.1

Hepatocellular carcinoma (HCC) surveillance with alpha-fetoprotein (AFP) has been recommended for persons with cirrhosis, but AFP level lacks the requisite sensitivity for the early detection of HCC.13 Other promising biomarkers, such as des-gamma carboxyprothrombin, lens culinaris agglutinin-reactive AFP, human hepatocyte growth factor, and insulin-like growth factor-1, have not been validated for clinical use. According to the National Cancer Institute, there is an urgent need for new biomarkers for early HCC.

CONCLUSIONS

It is hardly surprising that the search for effective diagnostic cancer markers that would lend themselves to simple, economical, and effective detection of early cancer has been so fruitless. If the last 30 years of brilliant discovery in molecular biology has proven anything, it is that oncogenes are a normal component of cellular machinery, which have gone awry to a state that is overexpressed, underexpressed, expressed inappropriately, in the wrong place at the wrong time at the wrong level, too much, or too little. If we accept this premise, perhaps we have the basis for an understanding of their nature and how to detect and analyze it. Because clearly a cancer cell is qualitatively different from a normal cell, and cancer cells most to be feared are malignant cells, which are qualitatively different on yet another level. Thus in principle at least, we should be able to distinguish them by biochemical means.

It is an obvious and inescapable fact that there is NO normal cell, or benign cancer cell, that forms masses that break apart, moves through the circulation, establishes itself in totally inappropriate regions of the body, abandons all (or almost all) of its normal functions and then embarks upon a self-destructive rampage of multiplication.


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