Melatonin in pathogenesis and therapy of cancer.

Melatonin is a neuroendocrine hormone secreted by the pineal gland to transduce the body's circadian rhythms. An internal 24 hour time keeping system (biological clock) regulated by melatonin, controls the sleep-wake cycle. Melatonin production is a highly conserved evolutionary phenomenon. The indole hormone is synthesized in the pinealocytes derived from photoreceptors. Altered patterns and/or levels of melatonin secretion have been reported to coincide with sleep disorders, jetlag, depression, stress, reproductive activities, some forms of cancer and immunological disorders. Lately, the physiological and pathological role of melatonin has become a priority area of investigation, particularly in breast cancer, melanoma, colon cancer, lung cancer and leukemia. According to the 'melatonin hypothesis' of cancer, the exposure to light at night (LAN) and anthropogenic electric and magnetic fields (EMFs) is related to the increased incidence of breast cancer and childhood leukaemia via melatonin disruption. Melatonin's hypothermic, antioxidant and free radical scavenging properties, attribute it to an immunomodulator and an oncostatic agent as well. Many clinical studies have envisaged the potential therapeutic role of melatonin in various pathophysiological disorders, particularly cancer. A substantial reduction in risk of death and low adverse effects were reported from various randomized controlled trials of melatonin treatment in cancer patients. This review summarizes the physiological significance of melatonin and its potential role in cancer therapy. Furthermore, the article focuses on melatonin hypothesis to represent the cause-effect relationship of the three aspects: EMF, LAN and cancer.

Clinical relevance of alternative splicing.

The unique phenomenon of alternative splicing is gathering concern due to its promising therapeutic potential. The human genome sequencing project suggests approximately 20,000-25,000 genes. Among these, about 35-60% of genes generate multiple mRNAs by alternative splicing mechanism and contribute to the diversity of the proteomic world. This 'gene shortfall' has ignited considerable interest in alternative RNA splicing. This process leads to expression of a single gene responsible for the transcription of different mRNA isoforms that might have multiple biological functions. The disruption of splicing pattern can produce aberrant splice variants, which are implicated in more than 50% of genetic disorders including cancer. Altered splice sites in neoplastic cell contribute to the development, progression and/or maintenance of tumorous growth. The repertoire of tumor-specific variant represents a potential marker in pharmacogenomic diagnostic relevance. Alternative splice isoforms have been analyzed serendipitously by qualitative gene profiling with in silico gene prediction software. Computational approach in identifying exonic splicing enhancers in genomic DNA and focus on microarray technology will elucidate differential expression of alternative splice variants. The antisense oligonucleotides modulate alternative splicing and engender the production of therapeutic gene products. Oligonucleotides have the potential to silence the mutations caused by aberrant splicing. The efficacy of the antisense oligonucleotides lies in the chemical configuration, affinity and delivery strategies. Hence the therapeutic potential of antisense oligonucleotides as modulators of aberrant alternative splicing would be a major challenge to the upcoming proteomic era.