Estimation and Regulation of DNA:
The Future Tool for Diagnosis, Treatment and Prognostic Evaluation of Cancer
- Part 3 -

JC Sanasam *

The combined strategies of anticancer therapy are likely to offer ultimately the most successful approach. The combined approach is likely to lead to reduction in the dose of each drug used and reduce the side effects of each individual agent.

In the last one and a half decade a vast amount of knowledge has been gained about altered DNA methylation patterns in human cancers. Identification, formulation and documentation of the tumor-specific methylation changes have been established. This information has led to potential clinical application in cancer diagnosis, prognosis, and therapeutics.

Axiomatically we can conjecture that making various combinations and permutations of the digits from 1 to 9, thousands to millions of numerical can be cast out. In like manner we can now chart out thousands and millions of DNA patterns from the 16 possible dinucleotide combinations composed out of the pairing of its four bases adenine, thymine, guanine and cytosine. This breakthrough in the biochemical engineering has brought us to a vast possibility and potentiality in the study, alterations, modifications and even creations of many tissue forms and character as well as in understanding life science.

DNA methylation is a covalent chemical modification, resulting from the addition of a methyl (CH3) group at the carbon 5 position of its cytosine ring. It is brought by a group of enzymes known as the DNA methyltransferases (DNMT).This cytosine methylation mostly occurs in the sequence context of some particular collections of nucleotides called the CpG islands. However it involves in traces some other nucleotides as well.

Approximately half of all genes in humans have CpG islands, and these are present on both housekeeping genes and genes with tissue-specific patterns of expression. From the identification of variations of these CpG islands methylation, knowledge on the possibility of developing cancers, progression of the stage of cancers, possibility of altering the progression so on and so forth can be determined.

Early Diagnosis of Cancer: It does not need to say again that early diagnosis is critical for the successful treatment of many types of cancer. The traditional methods of diagnosis such as cytology, serology, histopathology, immunohistochemistry, and so on, are still useful but molecular markers can extract and interpret much more detailed information. The methylation profile can distinguish tumor types and subtypes and perhaps the response to chemotherapeutic agents and survival.

Methylation changes often precede apparent malignant changes and thus are useful in early diagnosis of cancer. Sensitive detection of cancer cells, moreover, can be obtained from the plasma (the clear yellowish fluid portion of blood in which cells are suspended) in many cases. Examples are breast cancer, head and neck tumors, lung cancer, liver cancer, esophageal cancer, gastric cancer, colorectal cancer, bladder cancer, prostate cancer, gliomas.

In addition samples obtained by exfoliative cytology, endoscopic brush techniques, and biopsy, as well as urine, saliva, and sputum samples, also can be used. These are noninvasive or minimally invasive procedures and often easier to collect and process. The sensitivity and specificity of DNA methylation markers in cancer diagnosis depends on several factors, including the type of cancer and gene to be studied, the type of body fluid to be used, and the technique involved.

DNA Methylation as a Prognostic Marker: DNA methylation being closely related to the development of cancer, it would be interesting to know whether its presence or absence affects the prognosis as well. This can help taking up the initial treatment options, monitoring patient response to therapy, and predicting survival. Hyper or hypomethylation patterns, alterations of p12, p15, P16 genes and many other variations can render lots of information related to the severity, degree of malignancy and survival potentiality of patients. The methylation profile can also help in predicting response to a chemotherapeutic agent (drug used for treatment of cancer).

DNA Methylation and Novel Therapeutic Strategies: Researchers have done plenty of experiments using cell culture and they have found out that demethylating drugs can reverse the silencing of genes resulting from methylation. This potential to reverse DNA methylation and re-express the affected critical genes presents an attractive option for exploring clinical use in malignancies.

The commonly used drugs targeting methylation are azacytidine, decitabine, fazarabine, and dehydro-5-azacytidine. These are all derivatives of deoxycytidine with some modification at the fifth position in the pyrimidine ring. Other drugs include zebularine and antisense oligodeoxynucleotides. Histone deacetylase inhibitors also have been tried as potential chemotherapeutic agents.

How these agents act pharmacologically may not be the cup of tea for general readers and may be difficult for the general population to swallow. Further laboratory studies and clinical trials are still needed to fully establish the therapeutic efficacy of methylation inhibitors and their use in combination with histone deacetylases and convenient chemotherapeutic agents. That the widespread use of demethylating drugs can have serious side effects and even promote malignant transformations of genes is still under serious investigation; however things are yet in the positive direction.

The combined strategies of anticancer therapy are likely to offer ultimately the most successful approach. The combined approach is likely to lead to reduction in the dose of each drug used and reduce the side effects of each individual agent. How to combine the demethylating agents and histone deacetylase inhibitors with conventional chemotherapy to achieve the best outcome is still under serious investigation. If the exact methylation profiles of tumors are available and drugs targeting the specific genes are obtainable, then the treatment of cancer may become within easy reach of the therapists and the recipients as well.

The sad part is, in Manipur no inkling of this kind has so far come up on the surface from the governmental side as well as from the private sectors to be in touch with such new innovative modern discoveries of medicine and science whereas it is the corner stone of the latest finds worldwide. Of course to do so Manipur requires an adequate 24X7 power supply of 220 to 250 volts and a little of vision far beyond as an essential first step.

Concluded ...