Chemotherapy

Antifungal chemoprophylaxis in children and adolescents with haematological malignancies and following allogeneic haematopoietic stem cell transplantation: review of the literature and options for clinical practice

by Charalampos Dokos

BMI alterations during treatment of childhood ALL

by Charalampos Dokos

Back from the Brink: Biliary Stenting and Chemotherapy in Cholangiocarcinoma

by IOMC Conference

Smiley Rose Crane*, Jennelle Francis* and Ahmad Ridha Roney*
*Joint first authors, St.George’s University of London, UK
smiley_crane@hotmail.com

Pharmacogenetic analyses of cisplatin-induced nephrotoxicity indicate a renoprotective effect of ERCC1 polymorphisms.

by Valerie P. O'Brien

Aim: We investigated whether genetic polymorphisms may contribute to the interpatient variability of cisplatin-induced... more Aim: We investigated whether genetic polymorphisms may contribute to the interpatient variability of cisplatin-induced nephrotoxicity.

Patients & methods: Polymorphisms in the candidate genes GSTM1, GSTT1, OCT1, OCT2, LARP2, ERCC1, XRCC1 and EPO were analyzed for associations with nephrotoxicity in 79 cancer patients receiving cisplatin-containing chemotherapy.

Results: Higher cisplatin dose was associated with strongly decreased estimated glomerular filtration rates (eGFR) (r(2) = 0.205). Two highly genetically linked polymorphisms in the ERCC1 gene, 8092C>A and Asn118Asn, were significantly associated with change in eGFR, accounting for an additional 13% of interindividual variability. Homozygous carriers of the 8092A allele in ERCC1 showed no reduction in eGFR, compared with the 11.5% mean eGFR decrease in C allele carriers (p = 0.004). Homozygous carriers of the C allele of Asn118Asn showed no reduction in eGFR, compared with the 12.8% mean eGFR decrease seen in T allele carriers (p = 0.047). Polymorphisms in the other candidate genes were not associated with cisplatin-induced nephrotoxicity.

Conclusion: Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.

Original submitted 23 May 2011; Revision submitted 5 July 2011.

Initial Clinical Response" to Neoadjuvant Chemotherapy: An In-vivo Chemosensitivity Test for Efficacy in Patients with Advanced Breast Cancer.

by Saqib Mahmood

Khokher S, Mahmood S, Qureshi MU, Khan SA, Chaudhry NA.

Asian Pac J Cancer Prev. 2011;12(4):939-46.

Abstract
Neoadjuvant chemotherapy (NACT) is well established as the standard of care and initial management of... more Abstract
Neoadjuvant chemotherapy (NACT) is well established as the standard of care and initial management of choice for patients with advanced breast cancer (ABC). The response is however not uniform. The present study was an endeavor to develop a clinically applicable tool based on the available clinico-pathological data in the routine clinical setting to predict response to chemotherapy in breast cancer in a developing country. From 1st June 2005 to 30th June 2007, 149 patients registered at INMOL hospital with ABC at initial diagnosis having tumor size 5 cm or more and treated with FAC as NACT were prospectively included in the study to analyze association of response after first cycle of chemotherapy (initial clinical response) with that after the third cycle. Tumor measurements were done at base line (before starting chemotherapy), three weeks after the first course of chemotherapy and three weeks after the third course. Percentage change was calculated for the latter two stages. Clinical response was assessed according to WHO/UICC criteria. Pathological complete response (pCR) was based on the histopathology of the operative specimen after NACT. 67.1% patients (cCR 7.4%+cPR 59.7%) responded to chemotherapy while 32.9% (cSD 23.5%+cPD 9.4%) did not. pCR rate was 4%. No patient had initial clinical complete response while 23% had icPR, 74% had icSD and 3% had icPD. All patients with icPR responded to NACT (cCR 29%+cPR 71%) while 60% of icSD responded to chemotherapy (cCR 1%+cPR 59%) and 40% of icSD failed to respond (cSD 31%+cPD 9%). All patients with icPD developed cPD. The high sensitivity of initial clinical response for prediction of cCR and 100% specificity of icPD for prediction of cPD favors its incorporation in clinical practice, as an early predictor of response to NACT in ABC patients.

Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2

by Shirley Zhang

Platinum anticancer agents and antidepressants: desipramine enhances platinum-based cytotoxicity in human colon cancer cells

by Nicholas Pullen

Peyman K, Engelmann BJ, Pullen N, Stewart JK, Ryan JJ and Farrell NP
JBIC Journal of Biological Inorganic Chemistry, DOI: 10.1007/s00775-011-0836-1

A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant... more A unique synergistic effect on platinum drug cytotoxicity is noted in the presence of the tricyclic antidepressant desipramine. Desipramine is used for treating neuropathic pain, particularly in prostate cancer patients. The clinically used drugs cisplatin (cis-[PtCl(2)(NH(3))(2)]), oxaliplatin [1,2-diaminocyclohexaneoxalatoplatinum(II)], and the cationic trinuclear agent BBR3464 [{trans-PtCl(NH(3))(2)}(2)-μ-(trans-Pt(NH(3))(2)(H(2)N(CH(2))(6)NH(2))(2))](4+), which has undergone evaluation in phase II clinical trials for activity in lung and ovarian cancers, were evaluated. Surprisingly, desipramine greatly augments the cytotoxicity of all the platinum-based chemotherapeutics in HCT116 colorectal carcinoma cell lines. Desipramine enhanced cellular accumulation of cisplatin, but had no effect on the accumulation of oxaliplatin or BBR3464, suggesting that enhanced accumulation could not be a consistent means by which desipramine altered the platinum-drug-mediated cytotoxicity. The desipramine/cisplatin combination resulted in increased levels of p53 as well as mitochondrial damage, caspase activation, and poly(ADP ribose) polymerase cleavage, suggesting that desipramine may synergize with cisplatin more than with other platinum chemotherapeutics partly by activating distinct apoptotic pathways. The study argues that desipramine may be a means of enhancing chemoresponsiveness of platinum drugs and the results warrant further investigation. The results emphasize the importance of understanding the differential pharmacological action of adjuvants employed in combinations with cancer chemotherapeutics.

Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells

by K Brakora

Full text free

Ovarian cancer is currently the most lethal gynecologic malignancy in developed countries, and paclitaxel is a... more Ovarian cancer is currently the most lethal gynecologic malignancy in developed countries, and paclitaxel is a cornerstone in the treatment of this malignancy. Unfortunately, the efficacy of paclitaxel is limited by the development of drug resistance. Clinical paclitaxel resistance is often associated with ABCB1 (MDR1) overexpression, and in vitro paclitaxel resistance typically demonstrates overexpression of the ABCB1 gene. In this study, we demonstrate that paclitaxel-resistant cell lines overexpress both ABCB1 and ABCB4 (MDR3). To evaluate the role of these transporters in paclitaxel-resistant ovarian cancer cells, small interference RNAs (siRNAs) were used to target ABCB1 and ABCB4 RNA in the paclitaxel-resistant SKOV-3TR and OVCAR8TR ovarian cancer cell lines. Treatment of these lines with either chemically synthesized siRNAs or transfection with specific vectors that express targeted siRNAs demonstrated decreased mRNA and protein levels of ABCB1 or ABCB4. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays of siRNA-treated cells demonstrated 7- to 12.4-fold reduction of paclitaxel resistance in the lines treated with the synthesized siRNA of ABCB1 and 4.7- to 7.3-fold reduction of paclitaxel resistance in the cell lines transfected with siRNA of ABCB1 expressing vectors. ABCB4 siRNA-treated cell lines showed minor reduction in paclitaxel resistance. These results indicate that siRNA targeted to ABCB1 can sensitize paclitaxel-resistant ovarian cancer cells in vitro and suggest that siRNA treatment may represent a new approach for the treatment of ABCB1-mediated drug resistance.

GBP1 overexpression is associated with a paclitaxel resistance phenotype

by K Brakora

In the search for novel genes involved in the paclitaxel resistance phenotype, prior studies of gene expression in... more In the search for novel genes involved in the paclitaxel resistance phenotype, prior studies of gene expression in paclitaxel-resistant cell lines and their paired drug-sensitive parental lines using high-density Affymetrix GeneChip arrays identified guanylate-binding protein 1 (GBP1) gene as an overexpressed transcript. The GBP1 gene encodes a large GTPase that is induced by interferon gamma (IFN-γ) in a variety of eukaryotic cells. In this report we characterize GBP1 and demonstrate that GBP1 expression is consistently upregulated in 7 of 8 paclitaxel or doxorubicin-resistant human cancer cell lines as compared to its expression in the relevant drug-sensitive parental lines. Analysis of GBP1 expression using the Cancer Profiling Array showed that GBP1 is ubiquitously expressed with no significant difference in expression levels between normal and tumor tissue. Parallel analysis of the Cancer Cell Line Profiling Array determined that GBP1 expression in a majority of cell lines derived from human tumors of different tissue origin was induced to variable levels following exposure to multiple stress agents including paclitaxel and doxorubicin. Importantly, stable expression of a GBP1 transgene in the paclitaxel-sensitive ovarian cancer cell line OVCAR8 was sufficient to confer moderate paclitaxel resistance. Our data suggest that increased expression of the GBP1 gene may play an important role in the development of multi-drug resistance (MDR).

MM-TRAG (MGC4175), a novel intracellular mitochondrial protein, is associated with the taxol-and doxorubicin-resistant phenotype in human cancer cell lines

by K Brakora

In the search for novel genes involved in the taxol resistance phenotype, prior studies of gene expression in... more In the search for novel genes involved in the taxol resistance phenotype, prior studies of gene expression in taxol-resistant cell lines and their paired drug-sensitive parental lines using high-density Affymetrix microarrays identified MGC4175 as an overexpressed transcript. In this report, we characterize MGC4175 and demonstrate that seven of eight taxol- and doxorubicin-resistant cell lines overexpressed MGC4175 as compared to their chemotherapy naive parent lines. Sequence analyses of MGC4175 cDNA and the predicted amino acid sequence did not show significant homology to any known sequence or protein domain, with an open reading frame of 356 bp that is predicted to encode a protein product of 118 amino acids. Both the MGC4175 and MDR1 genes are located at chromosome position 7q21. Southern blot analysis demonstrated that a single copy of MGC4175 is present in the human genome, and MGC4175 overexpression is not caused by genomic amplification or gene arrangement. Human MGC4175 fused to the carboxy terminus of enhanced green fluorescent protein (EGFP) and expressed in U-2OS cells localized the protein to the perinuclear region with further studies colocalizing this protein to the mitochondria. The Cancer Profiling Arrays and the Cancer Cell Line Profiling Array demonstrated that MGC4175 is broadly expressed in various tissues with no significant difference of MGC4175 expression between chemotherapy naive tumor cells and normal cells. However, MGC4175 is overexpressed 1.2- to 12.3-fold after 48 h of taxol induction and 0.65- to 6.5-fold after doxorubicin induction in various human cancer cell lines. In light of the overexpression of MGC4175 in association with taxol exposure, drug resistance, the coexpression of MDR1 and the mitochondrial localization of its protein, we propose to name this transcript MDR1 and Mitochondrial Taxol Resistance Associated Gene (MM-TRAG) and suggest that MM-TRAG may play a role in the development of taxol resistance in human cancer.

BMS-247550 Bristol-Myers Squibb/GBF.

by K Brakora

Bristol-Myers Squibb and the German Research Centre for Biotechnology are developing BMS-247550 as one of a series of... more Bristol-Myers Squibb and the German Research Centre for Biotechnology are developing BMS-247550 as one of a series of epothilones, for the potential treatment of various forms of cancer. BMS-247550 had successfully completed phase I trials by September 2000 and by February 2001, phase II trials had been initiated for a variety of tumor types in collaboration with the National Cancer Institute; at this time, DNA filing was expected in 2003, and commercialization in 2004. By April 2002, phase I trials in children had also been initiated. As of May 2002, phase II studies had been conducted in patients with non-small-cell lung cancer and breast cancer.

Technology to Policy Case Study: Targeted Nanovector Chemotherapy

by Travis Horsley

Office of Policy Analysis and Research
Georgia Tech Research Institute
Spring 2009
By Alexandra Henke and Travis Horsley
Edited by PI Marlit Hayslett and Co-PI Jessica Pater

The T2P framework is designed to forecast potential public policy implications of emerging technologies using known... more The T2P framework is designed to forecast potential public policy implications of emerging technologies using known policy outcomes of preceding and analogous technologies. The purpose of this T2P case study is to forecast the potential policy outcomes of targeted nanovector chemotherapy by examining the policy outcomes of the preceding technology, traditional chemotherapy, and four analogous technologies: beneficial insect pest control, antibiotics, Six Sigma and computer virus removal software. The case study will show the step by step analysis of the technology using the T2P framework. It will begin with a brief background on the history and applications of targeted nanovector chemotherapy, then it will review the assumptions of the T2P framework in general and assumptions that were made in this particular analysis, and finally it will review the properties analysis of the emerging, preceding, and analogous technologies, and explain why these technologies are relevant for forecasting the public policy outcomes of targeted nanovector chemotherapy.

Current status of Chagas disease chemotherapy.

by Fredy RS Gutierrez

Guedes PM, Silva GK, Gutierrez FR, Silva JS.
Expert Rev Anti Infect Ther. 2011 May;9(5):609-20.

Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic... more Chagas disease affects 7.7 million people and 28 million people are at risk of acquiring the disease in 15 endemic countries of Latin America. Benznidazole and nifurtimox are drugs that have been used to treat the disease. However, both drugs induce severe side effects. Treatment with benznidazole has been recommended for the acute phase (0-4 months after infection), recent chronic phase (children 0-14 years of age, treated 4 months after infection) and congenital infection. Average cure rates for Chagas disease patients obtained from clinical trials were 97.9% (congenital infection, treatment performed 0-6 months of age), 71.5% (acute phase), 57.6% (recent chronic phase, children 0-13 years of age) and 5.9% (late chronic phase, great majority of patients between 15 and 69 years of age). Clinical evidence about the capacity of antiparasitic treatment to avoid, stop or revert heart pathology in indeterminate and cardiac chronic patients is contradictory. The investigation of novel therapeutic strategies against Chagas disease remains a priority in the research of tropical diseases. Unfortunately, Chagas disease remains neglected in the formulation of strategies toward control of this disease. This article focuses on current therapeutic approaches to Chagas disease.

Reversible Fanconi Syndrome Due to Lenalidomide

by Kenar Jhaveri

Severe Hyperkalaemia Resulting From Octreotide Use In a Haemodialysis Patient

by Kenar Jhaveri

Utilising handheld computers to monitor and support patients receiving chemotherapy: results of a UK-based feasibility study

by Lisa Kidd

PARP Inhibitor as an Effective Standard Treatment in Cancer with DNA Repair Defects

by Stephanie Sandvick

This was the speech I wrote and qualified for the 134th Interstate Oratory National Competition which took place at James Madison University in Harrisonburg, VA. I represented the state of North Dakota at this national rhetoric competition and as a result, the speech has been published in "Winning Orations of the Interstate Oratorical Association" for the year of 2011.

Today breast cancer is the second most diagnosed cancer in women, accounting for 1 in 4 cancers diagnosed. Some... more Today breast cancer is the second most diagnosed cancer in women, accounting for 1 in 4 cancers diagnosed. Some oncologists have suggested that the poor prognosis of certain cancers may be blamed on current standardized cancer treatments. PARP inhibitor, an anticancer drug that affects base excision repair in DNA of cancer cells has been a proposed solution to increasing cancer survival rates when used in conjunction with standardized cancer treatments. This speech discusses the problems associated with standardized cancer treatments and how PARP inhibitor can be a contributor to maximize these treatments.

Prolonged Succinylcholine Action During Electroconvulsive Therapy (ECT) After Cytarabine, Vincristine, and Rituximab Chemotherapy

by Ethan Bryson

Bryson EO, Aloysi AS, Perez A, Popeo D, Kellner C.
Journal of Electroconvulsive therapy, Jan 2011

Succinylcholine is a depolarizing neuromuscular blocker frequently used during electroconvulsive therapy. In most... more Succinylcholine is a depolarizing neuromuscular blocker frequently used during electroconvulsive therapy. In most patients, the duration of paralysis is brief, allowing for spontaneous respiration shortly after the therapy. We report a case of delayed return of neuromuscular function after succinylcholine administered during electroconvulsive therapy in a 72-year-old man receiving cytarabine, vincristine, and rituximab chemotherapy for chronic lymphocytic leukemia. We hypothesize that an interaction between succinylcholine and one of the chemotherapeutic agents caused the prolongation of paralysis and believe that this is the first reported case of prolonged duration of succinylcholine following this regimen of chemotherapy. Despite this unexpected prolonged neuromuscular blockade,
the patient could be treated uneventfully, with attention paid to his respiratory support and with subsequent succinylcholine dose titration to effect