Decitabine

PURPOSE OF REVIEW: Decitabine is a cytosine analogue synthesized in the 1960s that is currently enjoying a revival of interest prompted by the elucidation of DNA methylation inhibition as its major mechanism of action, along with increased understanding of the role of DNA methylation in epigenetic dysregulation in cancer. These advances have turned this agent from just another cytosine analogue into a targeted drug aimed at reversing epigenetic silencing in cancer cells. Here, recent clinical and translational studies with decitabine are reviewed. RECENT FINDINGS: Scientists are now taking a closer look at this drug as a targeted agent, with particular attention to schedules of administration and mechanisms of in vivo efficacy. Two phase II trials have reported substantial clinical activity of decitabine in the myelodysplastic syndrome and in chronic myelogenous leukemia. There is considerable interest in combining decitabine with histone deacetylase inhibitors and in using it to sensitize cells to chemotherapy or to biologic therapy. Finally, ongoing efforts are deciphering the in vivo mechanisms of responses seen after decitabine administration. SUMMARY: Decitabine, an old drug, has now made a comeback as a targeted agent and a prototype for epigenetic therapy in cancer. Doses, schedules of administration, and the development of rational combinations including this agent must all take this critical mechanism of action into account.     

Hypermethylation of CpG islands in the mouse asparagine synthetase gene: relationship to asparaginase sensitivity in lymphoma cells. Partial methylation in normal cells

We have sequenced the promoter region of the murine asparagine synthetase gene and examined its methylation profile in the CpG islands of L-asparaginase-sensitive 6C3HED cells (asparagine auxotrophs) and resistant variants (prototrophs). In the former, complete methylation of the CpG island is correlated with failure of expression of mRNA: cells of the latter possess both methylated and unmethylated alleles, as do cells of the intrinsically asparagine-independent lines L1210 and EL4. A similar phenomenon was seen in normal splenic cells of adult mice. This was age related: no methylation was found in weanlings, but up to 45% of gene copies in animals 18 weeks or older were methylated. It was also tissue related, with methylation occurring rarely in liver cells. The relationship of these changes to oncogenesis is considered.     

Cutaneous myiasis of the breast: mammographic and us features-report of five cases

Five patients with breast myiasis underwent mammography, and three also underwent ultrasonography (US). Mammography revealed indistinct masses in all patients, with associated pairs of microcalcifications in three. US showed each larva as a fusiform hyperechoic mass surrounded by a hypoechoic halo, which included larval movement in one patient. These imaging features of breast myiasis facilitate correct diagnosis.     

Ethical considerations in clinical pharmacogenomics research

In recent years there have been unprecedented advances in our understanding of the involvement of genetic polymorphisms in the response to drug therapies. Polymorphisms have been identified that lead to variable patient responses to several medications including cardiovascular, psychiatric, anti-infective and analgesic therapies. The potential for the development of customized, genotype-based therapies is scientifically and clinically attractive. However, these developments, although bearing scientific promise, raise ethical concerns for the conduct of research with human subjects, particularly with respect to confidentiality, risk-benefit analysis, DNA-banking and pharmacoeconomic issues. This article discusses some of the ethical considerations that are related to the use of pharmacogenomics in clinical research protocols.     

Distribution of neuronal receptors for nerve growth factor in the rat

To survey the distribution of neuronal receptors for NGF, sections of the rat brain, spinal cord, and peripheral ganglia were incubated in vitro with radioiodinated NGF and examined by autoradiography. NGF binds selectively with high affinity to most sympathetic neurons and many primary sensory neurons together with their intraspinal or intramedullary axons. In autoradiographs of the brain, labeled neuronal perikarya are seen in the basal forebrain, the caudate-putamen, the medulla oblongata, the ventral cochlear nucleus, and the dorsal nucleus of the lateral lemniscus. The distribution of neurons binding NGF resembles the distribution of cholinergic neurons in the forebrain, but these 2 systems overlap very little in the brain stem. In extracts of the brain or spinal cord enriched for plasma membranes, avid binding sites are regionally manifest with properties similar to those of fetal peripheral neurons. The localization of neurons expressing the high-affinity receptor for NGF defies simple correlation with neurotransmitter function or embryogenesis.