Markers Of Drug Response Research Articles

Chemoresponse assay for evaluating response to sunitinib in primary cultures of breast cancer

Purpose: Not all patient tumors respond equally to the same type of therapy. An in vitro chemoresponse assay that can suggest individualized tumor response to therapies, in this case sunitinib, can be a valuable guide for clinical decision-making.Experimental Design: The ChemoFx® drug response marker (DRM) (Precision Therapeutics, Inc.) was carried out on SK-OV-3 cells treated with sunitinib to establish appropriate dose ranges and assay thresholds, and to evaluate vendor supplies of sunitinib. Once reference values were determined, the assay was applied to eight different renal cell lines treated with sunitinib, each of which was subsequently classified into responsive, intermediate responsive, and non-responsive groups. Next, ex vivo tumor samples from 39 clinically diagnosed breast cancer patients were grown in culture and assayed for their response to sunitinib using ChemoFx.Results: The assay was shown to be sensitive and reproducible while differentiating renal cell lines based on sunitinib sensitivity and evaluating vendors’ supply of the compound. Of the cultured breast cancer tumor specimens treated with sunitinib, ChemoFx classified 7.6% as responsive (R), 20.5% of specimens as intermediate responsive (IR), and 71.7% as non-responsive (NR).Conclusions: Chemoresponse assay assessment is an effective tool for evaluating sunitinib sensitivity in cultured cell lines as well as ex vivo breast cancer samples. An in vitro assay that may indicate an individual patient’s clinical response to a chemotherapeutic agent can be beneficial in time, cost, and clinical outcome when therapeutic options are considered.

Acquired drug resistance in gynecologic cancer detected by drug response marker testing.

5068 Background: To compare in vitro drug response profiles in metachronous tumors (specimens from the same patient before and after chemotherapy) in an unselected population of gynecologic cancers...

Abstract 4114: Evaluation of ERCC1 expression and in vitro drug response to cisplatin based on human NSCLC cell lines and primary cultures of human lung cancers

Abstract Introduction: In vitro experimentation has been suggested as a rapid tool for identifying and evaluating biomarkers associated with drug response. Excision repair cross-complementation 1 (ERCC1) enzyme plays a rate-limiting role in the nucleotide excision repair pathway and its up regulation has been associated with resistance to platinum agents. Recent studies have suggested that low expression levels of ERCC1 are related to a better survival benefit from cisplatin-based chemotherapy among patients with advanced non-small cell lung carcinoma (NSCLC). This study evaluates the relationship between ERCC1 expression and in vitro drug response to cisplatin using an in vitro chemoresponse assay, ChemoFx® Drug Response Marker (DRM), in human NSCLC cell lines and primary cultures of human lung cancers. Methods: The ChemoFx® DRM was performed on 13 immortalized human NSCLC cell lines (NCI-H520, HOP_92, HOP-62, A549, Calu-3, HCC827, OK, NCI-H460, NCI-H596, NCI-H1666, EKVX, NCI-H358, and NCI-H1975) and 30 primary cultures established from de-identified lung cancer surgical specimens. Cells were treated with a 10-dose range of cisplatin for 72 hours before DAPI-nuclear staining and counting. Response Index scores (RI scores), which are derived from an area under the dose-response curve (AUC), were calculated on the resulting dose-response curves. Protein expression of ERCC1 was evaluated with In-Cell Western analysis. Pearson correlation coefficient was used to show the association between ERCC1 expression and in vitro drug response. Result: Increased ERCC1 expression was significantly associated with cisplatin resistance in the 13 immortalized NSCLC cell lines (r=−0.72, p=0.004). A similar trend was observed across 30 primary cultures of human lung cancers, but the association did not reach the level of significance (r=−0.22, p=0.24). Conclusion: Clinical observation of a negative correlation between ERCC1 expression level and improved survival benefit from cisplatin-based chemotherapy was mirrored by in vitro ChemoFx® DRM analysis with strong correlation in immortalized human NSCLC cell lines and in primary cultures from human lung cancers with a correlation trend. This result suggests the value of in vitro chemoresponse assay in identification and evaluation of biomarkers and their association with chemotherapeutic response. The less significant correlation in human lung cancer primary cultures indicated that ERCC1 alone may not be sufficient for clinical prediction of response in human lung cancers across different pathological subtypes and stages, and additional biomarkers may be involved. These results suggest the value of in vitro chemo response assay, in helping to determine cisplatin response in human lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4114. doi:10.1158/1538-7445.AM2011-4114

Consistency of In Vitro Chemoresponse Assay Results and Population Clinical Response Rates Among Women With Endometrial Carcinoma

There are a number of equally efficacious chemotherapy options for the treatment of women with endometrial cancer, all of which work in only a subset of those women with this disease. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. Such an assay should yield response rates similar to those found in treated patient populations. The purpose of this investigation was to determine whether the patterns of in vitro tumor response rates as determined by ChemoFx are consistent with expected population response rates. Nine hundred twenty-three tumor specimens from patients with high-risk early-stage, advanced stage, or recurrent endometrial cancer were sent for testing with the ChemoFx drug response marker from August 2, 2006, to August 31, 2009. Tumors were categorized as responsive (R), intermediately responsive (IR), or nonresponsive to each drug or combination tested. Response rates from clinical trials were identified and compared with the corresponding in vitro response rates. Of the 923 specimens received, 759 (82%) were successfully tested by ChemoFx. Of these, 755 were tested for at least 1 of 5 National Comprehensive Cancer Network-recommended endometrial cancer drugs. The response rates (R+IR) for these drugs were as follows: 66% carboplatin-paclitaxel, 48% carboplatin, 37% cisplatin, 23% doxorubicin, and 36% paclitaxel. Moreover, 20% of tumors were pan-sensitive (R or IR) to all 5 regimens tested, 27% were pan-resistant (nonresponsive), and 53% showed different degrees of response to different drugs. ChemoFx in vitro response rates were consistent with published population response rates, and the ChemoFx drug response marker may provide clinically useful information to better optimize individual chemotherapy for treatment of women with endometrial cancer.

An in vitro chemoresponse assay defines a subset of colorectal and lung carcinomas responsive to cetuximab

Cetuximab is a chimeric monoclonal antibody for the epidermal growth factor receptor (EGFR) that may provide benefit to select cancer patients; however, identification of the characteristics of those patients who may benefit from its use is not complete. The ChemoFx® drug response marker (DRM) is an in vitro assay that can provide drug response data on tumor specimens before any patient treatment is initiated. We determined the feasibility of using the ChemoFx DRM to test tumor samples for sensitivity to cetuximab. We exposed four non-small cell lung carcinoma (NSCLC) cell lines (H358, H520, HCC827, and H1666) to cetuximab and determined their sensitivity using the ChemoFx DRM and, in parallel, EGFR status using immunocytochemistry, Western blotting, and In-Cell WesternTM analysis. We used the ChemoFx DRM to determine cetuximab sensitivity of primary NSCLC and colorectal tumor samples. The ChemoFx DRM distinguished between cetuximab-sensitive and -resistant cell lines. Cetuximab sensitivity was not dependent on EGFR mutational status; H358 cells were non-responsive to cetuximab yet contain wild-type EGFR, whereas H1666 cells were intermediately responsive to cetuximab and contain wild-type EGFR. HCC827 (EGFR-mutant) cells were intermediately responsive and, as expected, H520 cells (EGFR-null) were non-responsive to cetuximab. ChemoFx-determined cetuximab sensitivity of primary NSCLC and colorectal tumor samples was 9.0% and 7.5%, respectively. Use of the ChemoFx DRM is feasible for determining cetuximab sensitivity. The ChemoFx-determined cetuximab responses of primary NSCLC and colorectal tumor specimens were similar to published response rates of patients to treatment with cetuximab monotherapy.

Comparison of signal transduction drug response markers in immortalized cell lines and primary patient specimens

Abstract Background: The epidermal growth factor pathway is an important driver of cancer growth. Erlotinib is a small molecule protein-kinase inhibitor targeting the epidermal growth factor receptor (EGFR) that may benefit a select subtype of cancer patients. However, identification of the characteristics of patients who may benefit from the use of erlotinib is not easy. Previous publication explored the activation of signal transduction proteins in the EGFR pathway as a method of determining erlotinib response and demonstrated that lung cancer cell lines characterized by increased pEGFR/pAKT ratios are more resistant to erlotinib. The aim of this study was to compare the activation of signal transduction markers in the EGFR pathway between immortalized cell lines and primary cultures of patient-derived tumor cells. Predictive potential of pEGFR/pAKT ratios in both immortalized cell lines and primary cultures of lung cancer cells was also compared. Methods: Western blotting and In-Cell western analysis were used to determine the activation state of the EGFR signaling pathway. Signaling pathway components were compared in the presence and absence of erlotinib treatment in immortalized lung cancer cell lines and primary cultures of lung cancer specimens. Chemosensitivity of cell lines and specimens to erlotinib was determined using an in vitro drug response marker. Cells were treated with a 10 dose concentration range of erlotinib for 72 hours and the remaining post-treatment live cells were enumerated by nuclear staining. Results: The pEGFR/pAKT ratio was increased in erlotinib-responsive immortalized cell lines when compared to non-responsive cell lines (p<0.05). This difference in pEGFR/pAKT ratio was significant after treatment with erlotinib as well. The difference in pEGFR/pAKT ratios in response to erlotinib treatment between erlotinib-responsive and non-responsive primary cultures of lung cancer cells was not, however, statistically significant. Conclusion: These studies confirmed that pEGFR/pAKT ratios may be indicative of erlotinib response in immortalized lung cancer cell lines. However, when evaluating the signal transduction markers in patient-derived primary cultures, no correlation with in vitro erlotinib response was found. These results highlight the value of using in vitro drug response markers, which utilize primary patient tissue, in the development of predictive biomarkers.

Chemosensitivity testing with ChemoFx and overall survival in primary ovarian cancer

We sought to determine the association between tumor responses in vitro to platinum therapy by using the ChemoFx drug response marker and overall survival (OS) after first-line platinum-based chemotherapy in patients with advanced-stage primary ovarian cancer (POC). Chemosensitivity testing was performed in vitro on tumors from 192 POC patients. Tumors were classified as responsive, intermediately responsive, and nonresponsive to chemotherapy. Physicians made all management decisions. Survival status was retrieved from the Social Security Death Index. OS was modeled using Cox proportional hazard regression analysis. Median OS was 72.5 months for patients with tumors categorized as responsive, 48.6 months for intermediately responsive, and 28.2 months for nonresponsive (P = .03; hazard ratio, 0.70; 95% confidence interval, 0.50-0.97). The ChemoFx prediction of responses to platinum agents was an independent predictor of OS. Results of chemosensitivity testing with a drug response marker for therapy was predictive of OS in POC patients.

Tumoral and tissue‐specific expression of the major human β‐tubulin isotypes

The beta-tubulins are microtubule components encoded by a multigene family, which produces slightly different proteins with complex expression patterns. Several widely used anticancer drugs base their activity on beta-tubulin binding, microtubule dynamics alteration, and cell division blockage. The expression of these drug targets in tumoral and normal cells could be of crucial importance for therapy outcome, unfortunately, the complex beta-tubulin expression patterns have been poorly characterized in human. In this study, we developed a quantitative RT-PCR technique that accurately determines the mRNA expression of the eight human beta-tubulin isotypes, encoding class I, IIa, IIb, III, IVa, IVb, V, and VI and applied it to 21 nontumoral tissues and 79 tumor samples belonging to seven cancer types. In the nontumoral tissues, we found that, overall, TUBB (I), TUBB2C (IVb), and TUBB6 (V) were ubiquitous, TUBB1(VI) was hematopoietic cell-specific, and TUBB2A (IIa), TUBB2B (IIb), TUBB3 (III), and TUBB4 (IVa) had high expression in brain; however, the contribution of the different isotypes to the total beta-tubulin content varied for each tissue and had a complex pattern. In tumoral tissues, most isotypes exhibited an altered expression in specific tumor types or related to tumoral characteristics. In general, TUBB3 showed a great increase in expression while TUBB6 expression was largely decreased in most tumors. Thus, normal tissues showed a complex beta-tubulin isotype distribution, which could contribute to the toxicity profile of the microtubule-binding drugs. In addition, the specific isotypes significantly altered in tumors might represent markers for drug response.

Medication use by ethnic and racial groups: policy implications

Ethnic and racial populations often use fewer appropriate pharmaceuticals to treat important diseases than the majority population. This reduced use is due in part to their relative sensitivity to the economic burden of cost sharing and to cultural beliefs regarding medications and disease. In addition, differences among racial and ethnic population groups in the metabolism, effectiveness, and side-effect frequencies of many important drugs have been reported. Failure to take these socioeconomic and physiological factors into account in the design of pharmaceutical management or reimbursement policies has the potential for compromised outcomes and for accentuating disparities in treatment. Cost-sharing levels should not be set so high as to reduce the filling or refilling of needed prescriptions by patients with limited incomes. Ethnic/racial variations in drug metabolism, sensitivity, and side effects should be considered when determining inclusions on drug formularies and preferred drug lists. Differences in metabolic pathways among drugs of a class, coupled with ethnic/racial differences in frequency of gene variation in these pathways, call for caution when implementing therapeutic substitution policies. As more physiological and genetic markers of drug responsiveness become available, the use of ethnic and racial designations should diminish and therapies can be optimized for all patients. Reports of different sensitivies to the actions and side effects of some drugs in minority populations indicate the need for well-designed clinical trials on effectiveness and optimal dosing of drugs in specific populations. Recommendations from comparative effectiveness studies based on trials that do not include minority populations may lead to compromised clinical outcomes in these groups, increased costs, and sustained disparities in healthcare.

G-protein beta3 subunit polymorphism and bleeding in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction 16 trial.

Variability in platelet response to antiplatelet drugs is heritable. A common single base substitution (825C>T) in the G-protein beta polypeptide 3 (GNB3) gene leads to alternative splicing (41-amino-acid deletion) of the human G-protein beta3 (Gbeta3) subunit. This truncated protein carried by GNB3 T allele carriers is linked to coronary artery disease and implicated as a genetic marker of drug response. Large studies of Caucasians associate T allele carriage with lower platelet reactivity. To evaluate whether the GNB3 genotype would predispose to bleeding in patients treated with a GPIIb/IIIa receptor antagonist. GNB3 genotype distribution was determined in DNA samples from patients in the orbofiban in patients with unstable coronary syndromes-thrombolysis in myocardial infarction (OPUS-TIMI) 16 genetic sub-study. Impact of genotype on the bleeding endpoint and the composite primary endpoint of death, myocardial infarction (MI), re-hospitalization for ischemia and urgent revascularization was estimated in the treatment and placebo arm. Out of 887 patients, 45.1% carried the GNB3 CC genotype, 44.5% CT and 10.4% TT. Interaction between T allele carriership and treatment for bleeding was significant (P = 0.008). This reflects the fact that GNB3 non-T carriers treated with orbofiban had no bleeding effect compared with placebo (RR = 0.92, 95% CI 0.55-1.55) whereas T carriers did (RR = 2.62, 95% CI 1.58-4.35, P < 0.001). Interaction between T allele carriership and treatment was not significant for the primary endpoint (P = 0.18) or MI (P = 0.69). The GNB3 T allele significantly increased bleeding in patients treated with the platelet antagonist orbofiban. Our findings suggest that risk of bleeding associated with an antiplatelet agent is heritable and may be dissociated from risk of thrombosis.

Identification of USP18 as an Important Regulator of the Susceptibility to IFN-α and Drug-Induced Apoptosis

Gene products that modify the apoptotic susceptibility of cancer cells may offer novel drug response markers or therapeutic targets. In this study, we probed the contribution of 53 different isopeptidases to apoptosis triggered by bortezomib and etoposide. USP18, a type I IFN-induced protein that deconjugates the ubiquitin-like modifier ISG15 from target proteins, was found to limit apoptotic susceptibility to IFN-alpha or bortezomib. Ablating USP18 in cells treated with IFN-alpha increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) production; upregulated expression of transcription factors IFN-regulatory factor (IRF)-1, IRF-7, and IRF-9; and promoted the extrinsic pathway of apoptosis. The proapoptotic effects of ablating USP18 were abrogated by FLIP overexpression or TRAIL silencing. However, in bortezomib-treated cells, weak spontaneous signaling from type I IFNs was implicated in the proapoptotic effect of USP18 ablation. Ectopic USP18 repressed apoptotic signaling by IFN-alpha, TRAIL, or bortezomib. Similar effects were produced by a catalytically inactive USP18 mutant, indicating that the antiapoptotic function of USP18 is independent of its catalytic activity. These findings suggest that USP18 may significantly limit operation of the extrinsic apoptotic pathway triggered by type I IFN and drugs.

In vitro chemoresponse assay results and population chemotherapy response rates in endometrial cancer

5503 Background: While a number of potentially active chemotherapeutic agents are available for the treatment of endometrial cancer, some therapies may not be effective in all women. An in vitro assay performed before therapy initiation to identify the drug(s) most likely to be effective for the individual patient would have clinical utility. The primary objective of this study was to determine whether the results from an in vitro chemoresponse assay are similar to the published population response rates for endometrial cancer. Methods: Tumor specimens were collected from Dec 1, 2007 to July 15, 2008 from 405 consecutive patients with endometrial carcinoma and were tested in vitro for a response by using the ChemoFx assay. Tumors were categorized prospectively as responsive (R), intermediately responsive (IR) or nonresponsive (NR) to each drug or combination tested. The in vitro response rates were compared to reported response rates from clinical trials. Results: FIGO stage distribution was 171 stage I patients, 32 stage II patients, 106 stage III patients, 57 stage IV patients, 37 recurrent patients, and 2 unknown patients. The assay was successfully completed for 360 (89%) cases. The majority of tumors (73%) exhibited varying degrees of responsiveness to different drug(s). No significant difference in response rate was observed between primary and recurrent tumors or between stage I/II and III/IV tumors. Conclusions: In vitro tumor response rates were similar to reported treatment response rates for all treatments except single-agent carboplatin. A drug response marker can provide clinically useful information to optimize individual chemotherapy regimens for women with endometrial cancer. [Table: see text] [Table: see text]

Genotype-based therapeutic approach for colorectal cancer: state of the art and future perspectives

Background: There is a considerable need to increase efforts in maximizing clinical outcome in the treatment of colorectal cancer, and the identification of genetic factors underlying drug response seems to be one of the most promising areas in this research field. Methods: Clinical trials and pharmacogenetic association studies were reviewed to offer an overview of the most commonly reported polymorphisms in candidate genes critically involved in the response to the chemotherapeutics used at present in the management of colorectal cancer. Results: Several studies investigating the association between genotype and therapeutic results show contrasting data, thus determining increasing uncertainty in the identification of reliable predictive genetic markers of drug response. However, some of the genetic variations identified in genes encoding thymidylate synthase, dihydropyrimidine dehydrogenase, glutathione S-transferase pi, and uridine diphosphate glucosyltransferase 1A1 seem to be promising predictors of drug efficacy and/or toxicity. Conclusion: Additional investigation is needed to validate fully the clinical relevance of individual genetic differences in the variability of drug response. It is hoped that this knowledge base will offer, in the not too distant future, the opportunity to overcome the empirical trial-and-error method in favor of therapeutic drug optimization based on individual genetic make-up.

Race-based therapeutics

The issue of race in medicine is problematic. Race is not a physiologic grouping, and all persons of a given race do not necessarily share the same clinical phenotype or genetic substrate. Despite clear signals that certain risk factors and diseases vary as a function of race, translating those differences into race-based therapeutics has been awkward and has done little to change the natural history of cardiovascular disease as it affects special populations. Among the varied special populations, the African American population appears to have the most significant and adverse variances for cardiovascular disease as well as worrisome signals that drug responsiveness varies. Recent guideline statements have now acknowledged certain treatment options that are most appropriate for African Americans with cardiovascular disease, especially hypertension and heart failure. As more physiologic markers of disease and drug responsiveness become available, the need for racial designations in medicine may lessen, and therapies can be optimized for all patients without regard to race or ethnicity.

Symptomatic Treatment of Alzheimer's Disease: Identification of Biomarkers to Aid Translation from Bench to Bedside

In the absence of robust pharmacodynamic markers, the potential success of novel therapeutic agents for the symptomatic relief of Alzheimer's disease is largely unknown until the drugs enter relatively large studies, assessing clinical outcome over a 6-month period. In order to increase the efficiency of future clinical development there is, therefore, a need to identify pharmacodynamic markers of drug response, pharmacodynamic models that allow early prediction of efficacy and markers to aid the stratification of the patient population. Using literature available from cholinesterase inhibitors, memantine and Ginkgo biloba, this review focuses on the identification of potential pharmacodynamic markers/models and highlights the utility of these end points throughout the drug discovery process, from preclinical to clinical development.

Genome‐wide screening of loci associated with drug resistance to 5‐fluorouracil‐based drugs

Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response.

Quantitation of peripheral blood markers of rat experimental autoimmune encephalomyelitis

Identification and quantitation of peripheral blood non-invasive, cell-surface markers of EAE disease activity and drug response would facilitate the preclinical development of potential therapeutics. Towards this end, we characterized the influx of immune mediators into spinal cords of diseased rats to establish the kinetics of T cell and monocyte-mediated inflammation. We then examined the periphery for regulation of T cell and monocyte activation. We report increased CD80 and VLA-4 expression on peripheral blood monocytes (PBM) during the onset and peak of experimental disease scores. Increased CD4+, CD62L − and CD4+, CD134+ T cells were detected only at disease peak, not during disease onset. PBM CD80 expression was significantly inhibited in CSA-treated animals, but increased in Dex-treated animals. PBM VLA-4 expression was unaffected by drug treatment. Both CSA and Dex inhibited CD62L shedding and CD134 expression on peripheral CD4+ T cells. These results identify quantitative, peripheral markers of disease activity and drug response.

Epigenetic Markers and Response to Chemotherapy in Cancer

The last ten years has seen an explosion in interest in epigenetic mechanisms of control of gene expression. This is particularly true in the field of cancer research where epigenetic alterations are now regarded as equally important as genetic alterations in the development and progression of cancer. Of particular interest is altered DNA methylation, which is a key feature of essentially all tumour types. Aberrant methylation of CpG islands represents an ideal candidate for both diagnostic and prognostic markers in cancer. It is highly prevalent, very largely tumour specific and potentially far more readily detectible than most genetic alterations. This review will discuss the genes already identified as potential epigenetic markers of drug response, as well as the rapidly improving technology for detection of methylation which has greatly expanded the potential sources of tumour specific DNA that can be used for epigenetic marker analysis.

Pharmacogenetics in Affective Disorders: A Drug Response Approach

Affective disorders, including unipolar (UP) disorder and bipolar (BP) disorder are among the most important causes of death and disability worldwide and result in high costs in terms of morbidity as well as mortality. Although the etiology and pathophysiology is widely unknown, family-, twin- and adoption studies argue for a strong genetic determination of these disorders. These studies indicate that there is between 40-85% heritability for these disorders but point also to the importance of environmental factors. Despite the availability of a wide range of different drugs, about 30-50% of patients do not respond properly to acute treatment. Here we provide an overview of genetic drug response markers for affective disorder. Central in review is the question if individual therapeutic outcome for a given treatment can be predicted using genetic markers? An overview of pharmacogenetic and pharmacogenomic approaches is described for selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), and mood stabilizing drugs in relation to each of the major candidate genes for affective disorders. Keywords: Pharmacogenetics, drug response, affective disorders, candidate genes, review

In vitro Drug Response and Molecular Markers Associated with Drug Resistance in Malignant Gliomas

Drug resistance in malignant gliomas contributes to poor clinical outcomes. We determined the in vitro drug response profiles for 478 biopsy specimens from patients with the following malignant glial histologies: astrocytoma (n = 71), anaplastic astrocytoma (n = 39), glioblastoma multiforme (n = 259), oligodendroglioma (n = 40), and glioma (n = 69). Samples were tested for drug resistance to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, dacarbazine, paclitaxel, vincristine, and irinotecan. Biomarkers associated with drug resistance were detected by immunohistochemistry, including multidrug resistance gene-1, glutathione S-transferase pi (GSTP1), O(6)-methylguanine-DNA methyltransferase (MGMT), and mutant p53. In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance. Assessment of in vitro drug response and profiles of relevant tumor-associated biomarkers may assist the clinician in stratifying patient treatment regimens.