| Part one. The pharmacogenetics of treatment resistant depression . Major depression is a severe and disabling mood disorder for which there is no cure. Although selective serotonin reuptake inhibitors (SSRIs) have been successful in the treatment of major depression, a subset of patients (∼40%) is nonresponsive to drug therapy. Because the effect of poor treatment outcome contributes substantially to the morbidity and mortality associated with major depressive disorder, our goal was to identify genetic polymorphisms that might be used to predict outcome to SSRI treatment. Based on the observation that antidepressants exert their therapeutic effects through various biochemical pathways, we hypothesized that multiple genetic factors might contribute to the pathology of treatment resistant depression. Our research involves the use of the polymerase chain reaction to screen for polymorphisms in genes encoding the serotonin transporter, the serotonin receptor 1A, and monoamine oxidases A and B. Our results indicate that specific alleles of a serotonin transporter polymorphism and a monoamine oxidase B polymorphism are each of predictive value in determining SSRI response. More importantly, the significance level of association is increased dramatically when the two alleles are simultaneously present in individual research subjects. A total of 46% of SSRI responders, 75% of partial responders, and 90% of non-responders were found to possess this combination (n = 100, p = 0.0008), yielding 61 success in the prediction of poor response. Our long term goals involve the development of clinical screening method to expedite appropriate pharmacotherapy and positive treatment outcomes for refractory depressed patients.; Part two. DNA interaction and photocleavage by di- and tetracationic intercalants . Intercalators that cleave DNA are important as structural probes and as effective antitumor agents. Light-mediated DNA cleavage has rendered certain intercalators to be attractive tools for applications in photodynamic therapy. To this end, we have evaluated the photonicking and DNA binding properties of a series of putative mono-, bis-, and threading intercalators containing viologen linked to one or two phenazine, naphthalene, or crown ether subunits. We have demonstrated that very low concentrations of several of these compounds effect efficient photocleavage of double-stranded plasmid pUC19 DNA and single-stranded bacteriophage M13mp18 DNA at near physiological conditions of temperature and pH. Mechanistic studies suggest that singlet oxygen, direct electron transfer deoxyribose might play roles in the observed DNA photocleavage. Our biophysical data point to intercalative and electrostatic binding of several of these di- and tetracationic compounds to DNA. Furthermore, we have found that the ordering of photocleavage efficiency approximates relative DNA binding affinities and that the dicationic phenazine bisintercalator appears to perturb DNA structure to a higher degree than three known anticancer intercalators daunomycin, echinomycin and nogalamycin. The above results may serve as a basis for further evaluation of the potential applications of these compounds in photodynamic therapy. |
