Background: High-dose chemotherapy in the adjuvant treatment of breast cancer has been abandoned by many. Patients and methods: 885 patients with stage III primary breast cancer and four or more axillary lymph node metastases were randomised to receive either five courses of FEC (fluorouracil, epirubicin and cyclophosphamide) followed by radiation therapy ... read more and tamoxifen, or the same treatment but with high-dose alkylating chemotherapy (cyclophosphamide, thiotepa and carboplatin) replacing the fifth course of FEC. Of these patients, 621 had HER2/ neu-negative disease, as determined by immunohistochemistry and chromogenic in situ hybridisation. Results: At a median follow-up of 84 months, a trend for a better relapse-free survival was observed in the high-dose arm: (hazard ratio (HR) 0.84, P = 0.076, two-sided). The 621 patients with HER2/neu-negative disease benefited from high-dose therapy, while patients with HER2/neu-positive disease did not (test for interaction, P = 0.006). ...
This trial is investigating the tolerability of irinotecan, temozolomide and bevacizumab in combination with existing high dose alkylator based chemotherapy for
Introduction: After lymphoma the risk of secondary cancer namely lung cancer increases. Treatment (alkylating agents, radiotherapy) and smoking are known risk factors. Aims: To report on patients with lung cancer (LC) after lymphoma (LY), focusing on disease characteristics, detection methods and clinical outcomes. Methods: Retrospective study of patients diagnosed in a single institution with LC and previous LY from 1992 to 2012. Data regarding LY characteristics and treatment, smoking history and LC stage, histology and survival were obtained from medical records. Results: Of the 44 patients 43% had Hodgkin and 57% non Hodgkin lymphoma. All had known risk factors: 13 (30%) thoracic radiotherapy, 21 (48%) alkylating chemotherapy, 34 (75%) smoking habits. Median time between diagnoses was 9,5 years (±9.3).Thirteen were female (30%). Median age at LC diagnosis was 60 years (±13). Stage distribution was: 21(48%) IV, 10(23%) III; 13(30%) I/II. PS was 0/1 in 36(81%) patients. Diagnosis was ...
GyrI-like proteins are widely distributed in prokaryotes and eukaryotes, and recognized as small-molecule binding proteins. Here, we identify a subfamily of these proteins as cyclopropanoid cyclopropyl hydrolases (CCHs) that can catalyze the hydrolysis of the potent DNA-alkylating agents yatakemycin (YTM) and CC-1065. Co-crystallography and molecular dynamics simulation analyses reveal that these CCHs share a conserved aromatic cage for the hydrolytic activity. Subsequent cytotoxic assays confirm that CCHs are able to protect cells against YTM. Therefore, our findings suggest that the evolutionarily conserved GyrI-like proteins confer cellular protection against diverse xenobiotics via not only binding, but also catalysis.
PURPOSE: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. EXPERIMENTAL DESIGN: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. RESULTS: Inactivation of the MGMT gene by promoter methylation was associated with longer survival (P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation (
Tumor recurrence after initial treatment with radiation and temozolomide is the major cause of mortality for patients with glioblastomas, yet recurrences are understudied because of the dearth of matched tumors samples. This is of particular concern because temozolomide treatment profoundly affects the tumors evolution as evidenced by dramatic alterations in the genomic landscape of recurrent tumors compared with their primary tumor counterparts (65). A big effort has been made recently to understand this evolutionary process by comparing the genomic and proteomic profiles of primary versus recurrent tumors and correlating these datasets with treatment regimens, radiologic data, and clinical history (65-67). However, in these studies, no functional assays were carried out to understand mechanisms of temozolomide resistance due to the lack of matching primary and recurrent cell lines. We developed an in vivo model of tumor recurrence in mice that allows us to understand temozolomide resistance ...
Tumor recurrence after initial treatment with radiation and temozolomide is the major cause of mortality for patients with glioblastomas, yet recurrences are understudied because of the dearth of matched tumors samples. This is of particular concern because temozolomide treatment profoundly affects the tumors evolution as evidenced by dramatic alterations in the genomic landscape of recurrent tumors compared with their primary tumor counterparts (65). A big effort has been made recently to understand this evolutionary process by comparing the genomic and proteomic profiles of primary versus recurrent tumors and correlating these datasets with treatment regimens, radiologic data, and clinical history (65-67). However, in these studies, no functional assays were carried out to understand mechanisms of temozolomide resistance due to the lack of matching primary and recurrent cell lines. We developed an in vivo model of tumor recurrence in mice that allows us to understand temozolomide resistance ...
All patients entering this study will initially undergo combined modality treatment with concurrent radiation therapy + temozolomide. Four weeks after completing radiation therapy, patients will begin 6 months of follow-up treatment with oral temozolomide plus sorafenib.. Combined Modality Therapy - Radiation Therapy Radiotherapy must begin within ≤ 6 weeks of surgery. One treatment of 2.0Gy will be given daily 5 days per week for a total of 60.0Gy over 6 weeks. Temozolomide 75mg/m2 PO will be given daily, beginning on the first day of radiation therapy and continuing through the last day of radiation therapy.. After completion of combined modality therapy, patients will have 4 weeks without any therapy.. Systemic Therapy Beginning 4 weeks after the completion of radiation therapy, patients will receive 6 months of treatment with temozolomide and sorafenib. Temozolomide 150mg/m2 orally will be administered days 1-5, and repeated every 28 days for 6 courses. Sorafenib 400mg PO bid will be ...
Purpose In this large cohort of Hodgkins lymphoma survivors with long follow-up, we estimated the impact of treatment regimens on premature ovarian failure (POF) occurrence and motherhood, including safety of nonalkylating chemotherapy and dose-response relationships for alkylating chemotherapy and age at treatment. Patients and Methods The Life Situation Questionnaire was sent to 1,700 women treated in European Organisation for Research and Treatment of Cancer and Groupe dEtude des Lymphomes de lAdulte trials between 1964 and 2004. Women treated between ages 15 and 40 years and currently not using hormonal contraceptives (n = 460) were selected to assess occurrence of POF. Cumulative POF risk was estimated using the life-table method. Predictive factors were assessed by Cox regression analysis. Results Median follow-up was 16 years (range, 5 to 45 years). Cumulative risk of POF after alkylating chemotherapy was 60% (95% CI, 41% to 79%) and only 3% (95% CI, 1% to 7%) after nonalkylating ...
Single-agent docetaxel (Taxotere) has been shown to be highly active in metastatic breast cancer, with an overall response rate of 47%, median time to progression of 4 months, and survival of 10 months when administered as 1
Background: Temozolomide (TMZ) is the most widely used drug to treat glioblastoma (GBM), which is the most common and aggressive primary tumor of the Central Nervous System and one of the hardest challenges in oncotherapy. TMZ is an alkylating agent that induces autophagy, apoptosis and senescence in GBM cells. However, therapy with TMZ increases survival after diagnosis only from 12 to 14.4 months, making the development of combined therapies to treat GBM fundamental. One candidate for GBM therapy is Resveratrol (Rsv), which has additive toxicity with TMZ in several glioma cells in vitro and in vivo. However, the mechanism of Rsv and TMZ additive toxicity, which is the aim of the present work, is not clear, especially concerning cell cycle dynamics and long term effects. Methods: Glioma cell lines were treated with Rsv and TMZ, alone or in combinations, and the induction and the role of autophagy, apoptosis, cell cycle dynamics, protein expression and phosphorylation status were measured. We ...
By sacrificing its only alkyl component to the TMZ-induced lethal depletion of alkyl products on tumoural DNA, MGMT serves as a suicidal DNA repair enzyme. Theoretically, this irreversible depletion of the MGMT protein could be exploited by increasing tumoural exposure to TMZ. The effect might be even more prominent when MGMT promoter is hypermethylated, although the impact of MGMT promoter methylation could not be demonstrated in the present study. Nonetheless this mechanism also accounts for myelosuppression, the main concern of long-term use of TMZ, since MGMT protein in normal cells can also be depleted by TMZ. It is more common in haematopoietic stem cells contributing to toxicity for patients using this alkylating agent.3 In a cohort that comprised 114 patients, 39 (34%) were observed to have CTCAE grade 3 haematological toxicity during administration of TMZ. The study included all patients who received 1 to 57 cycles of TMZ.8 The French SV3 Study also evaluated the effect of prolonged TMZ ...
A Randomized, Placebo Controlled Phase IIb/III Study of ABT-414 with Concurrent Chemoradiation and Adjuvant Temozolomide in Subjects with Newly Diagnosed Glioblastoma (GBM) with Epidermal Growth Factor Receptor (EGFR) Amplification (Intellance 1)
Alkylating Antineoplastic Agents: A class of drugs that differs from other alkylating agents used clinically in that they are monofunctional and thus unable to cross-link cellular macromolecules. Among their common properties are a requirement for metabolic activation to intermediates with antitumor efficacy and the presence in their chemical structures of N-methyl groups, that after metabolism, can covalently modify cellular DNA. The precise mechanisms by which each of these drugs acts to kill tumor cells are not completely understood. (From AMA, Drug Evaluations Annual, 1994, p2026)
Title:A Short Review on the Synthetic Strategies of Duocarmycin Analogs that are Powerful DNA Alkylating Agents. VOLUME: 15 ISSUE: 5. Author(s):Pravin C. Patil, Vijay Satam and Moses Lee. Affiliation:Department of Chemistry, Georgia State University, Atlanta, GA 30303, USA.. Keywords:Antitumor-antibiotics, apoptosis, centanamycin, duocarmycins, tafuramycin A.. Abstract:The duocarmycins and CC-1065 are members of a class of DNA minor groove, AT-sequence selective, and adenine-N3 alkylating agents, isolated from Streptomyces sp. that exhibit extremely potent cytotoxicity against the growth of cancer cells grown in culture. Initial synthesis and structural modification of the cyclopropa[c] pyrrolo[3,2-e]indole (CPI) DNA-alkylating motif as well as the indole non-covalent binding region in the 1980s have led to several compounds that entered clinical trials as potential anticancer drugs. However, due to significant systemic toxicity none of the analogs have passed clinical evaluation. As a result, ...
This randomized phase II/III trial is studying vorinostat, temozolomide, or bevacizumab to see how well they work compared with each other when given together with radiation therapy followed by bevacizumab and temozolomide in treating young patients with newly diagnosed high-grade glioma. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high-energy x-rays to kill tumor cells. It is not yet known whether giving vorinostat is more effective then temozolomide or bevacizumab when given together with radiation therapy in treating ...
Phase II: Primary Objectives: -To determine the effectiveness of dasatinib (Sprycel) with radiotherapy (RT) and 6 weeks of concomitant temozolomide (TMZ)
Temozolomide is used in the treatment of brain tumor.get complete information about temozolomide including usage, side effects, drug interaction, expert advice along with medicines associated with temozolomide at 1mg.com
Clinical trial for Malignant neoplasm of brain , An Investigational Immuno-therapy Study of Temozolomide Plus Radiation Therapy With Nivolumab or Placebo for Newly Diagnosed Patients With Glioblastoma (GBM a Malignant Brain Cancer)
Clinical trial for Malignant neoplasm of brain , An Investigational Immuno-therapy Study of Temozolomide Plus Radiation Therapy With Nivolumab or Placebo for Newly Diagnosed Patients With Glioblastoma (GBM a Malignant Brain Cancer)
Radiation Therapy or Radiation Therapy and Temozolomide or Temozolomide Alone in Treating Patients With Newly Diagnosed Anaplastic Glioma This study is…
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DI-fusion, le Dépôt institutionnel numérique de lULB, est loutil de référencementde la production scientifique de lULB.Linterface de recherche DI-fusion permet de consulter les publications des chercheurs de lULB et les thèses qui y ont été défendues.
This is a non-randomized two-part study of MK-4827 given with temozolomide in participants with advanced cancer. In Part A of the study, the dose-limiti
Research paper that shows Temozolomide coupled with transporter molecules for drug delivery results in increased efficiency in cancer cell lines and lower toxicity in normal cells. ...
Carmustine with NDC 68475-503 is a a human prescription drug product labeled by Navinta Llc. The generic name of Carmustine is carmustine.
Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors. Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor
Metronomic cyclophosphamide given on an intermittent, 6-day repeating schedule, but not on an exposure dose-equivalent daily schedule, activates an anti-tumor innate immune response that leads to major regression of large implanted gliomas, without anti-angiogenesis. Mice bearing implanted 9L gliomas were used to investigate the effects of this 6-day repeating, immunogenic cyclophosphamide schedule on myeloid-derived suppressor cells, which are pro-angiogenic and can inhibit anti-tumor immunity, and to elucidate the mechanism whereby the innate immune cell-dependent tumor regression response to metronomic cyclophosphamide treatment is blocked by several anti-angiogenic receptor tyrosine kinase inhibitors. Intermittent metronomic cyclophosphamide scheduling strongly increased glioma-associated CD11b+ immune cells but not CD11b+Gr1+ myeloid-derived suppressor cells, while bone marrow and spleen reservoirs of the suppressor cells were decreased. The inhibition of immune cell recruitment and tumor
A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma Temozolomide is an alkylating agent with activity in the treatment of melanoma metastatic to the brain. Lomustine is a nitrosurea that crosses the blood brain barrier and there is evidence to suggest that temozolomide may reverse resistance to lomustine. A multicentre phase I/II study was conducted to assess the maximum-tolerated dose (MTD), safety and efficacy of the combination of temozolomide and lomustine in melanoma metastatic to the brain. Increasing doses of temozolomide and lomustine were administered in phase 1 of the study to determine the MTD. Patients were treated at the MTD in phase II of the study to six cycles, disease progression or unacceptable toxicity. Twenty-six patients were enrolled in the study. In phase I of the study, the MTD was defined as temozolomide 150 mg m(-2) days 1-5 every 28 days and lomustine 60 mg m(-2) on day 5 every 56 days. Dose-limiting ...
TY - JOUR. T1 - Inhibition of STAT3 reverses drug resistance acquired in temozolomide-resistant human glioma cells. AU - Lee, Eun Sang. AU - Ko, Kyung Kon. AU - Joe, Young Ae. AU - Kang, Seok Gu. AU - Hong, Yong Kil. PY - 2011/1/1. Y1 - 2011/1/1. N2 - The alkylating agent temozolomide (TMZ) is an effective drug used for the treatment of malignant gliomas. However, tumor relapse combined with the development of drug resistance remains a significant problem. To clarify the mechanism of the resistance of glioma cells to TMZ chemotherapy, TMZ-resistant glioma cell lines (TR cells) were generated using U373 and U251 human glioma cells, and TMZ-resistance was confirmed via viability and apoptosis assays. The TMZ-resistance of TR cells was not associated with the TMZ-resistance molecule O6-methylguanine-DNA-methyltransferase. Notably, the expression level of signal transducers and activators of transcription 3 (STAT3) and serine 727-phosphorylated STAT3 (pSTAT3-Ser727) was highly increased in TR cells, ...
Clinically achievable concentrations of temozolomide (TMZ) produce cytotoxic effects only in mismatch repair (MMR)-proficient cells endowed with low O6-methylguanine-DNA methyltransferase (MGMT) activity. Aim of the present study was to investigate the molecular mechanisms underlying acquired resistance of melanoma cells to TMZ and the effect of O6-benzylguanine (BG), a specific MGMT inhibitor, on the development of a TMZ-resistant phenotype. Three MMR-proficient melanoma cell clones with low or no MGMT activity were treated daily for 5 days with 50 µmol/l TMZ, alone or in combination with 5 µmol/l BG. Parental clones and sublines established after one or four cycles of treatment were analyzed for sensitivity to TMZ or TMZ+BG and for other parameters. The sublines established after one cycle of TMZ or TMZ+BG exhibited a marked increase in MGMT activity and resistance to TMZ alone. BG only partially reversed acquired resistance to the drug. In some cases, alterations in the MMR system accounted ...
... definition, any of various potentially cytotoxic, carcinogenic, and mutagenic substances: used therapeutically to destroy cells, especially proliferating cancer cells. See more.
Glioblastoma multiforme (GMB) is the most malignant and common type of all astrocytic tumors. Current standard of care entails maximum surgical resection of the tumor, followed by radiotherapy and chemotherapy, usually by the alkylating agent Temozolomide (TMZ). Despite this aggressive combination t …
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CAPTEM een combinatie behandeling van Xeloda - capecitabine met temozolomide - temodal zorgt voor spectaculaire resultaten - 97% bereikte minimaal duurzame stabiele ziekte - bij patiënten met alvleesklierkanker (NET tumoren), carcinoid, schildkliertumoren en hypofyse tumoren, ontstaan vanuit neuro endocriene afkomst, welke allemaal uitbehandeld waren. Nieuwe studies toegevoegd. Artikel update 22 december 2018
BACKGROUND. Temozolomide (TMZ) is one of the most potent chemotherapy agents for the treatment of glioblastoma. Unfortunately, almost half of glioblastoma tumors are TMZ resistant due to overexpression of methylguanine methyltransferase (MGMThi). Coadministration of O6-benzylguanine (O6BG) can restore TMZ sensitivity, but causes off-target myelosuppression. Here, we conducted a prospective clinical trial to test whether gene therapy to confer O6BG resistance in hematopoietic stem cells (HSCs) improves chemotherapy tolerance and outcome.. METHODS. We enrolled 7 newly diagnosed glioblastoma patients with MGMThi tumors. Patients received autologous gene-modified HSCs following single-agent carmustine administration. After hematopoietic recovery, patients underwent O6BG/TMZ chemotherapy in 28-day cycles. Serial blood samples and tumor images were collected throughout the study. Chemotherapy tolerance was determined by the observed myelosuppression and recovery following each cycle. Patient-specific ...
Enter Tumor Treating Fields (TTF): a little bit science fiction, a little bit science fact. I have to admit I was very skeptical when I first heard of the technology, and was even less enthused when I saw what a nuisance it is for patients - but it works. In 2015, investigator Roger Stupp (who developed temozolomide treatment in the first place) showed that adding TTF to standard treatment improved median overall survival from 16.6 to 19.6 months, and improved a patients chances of surviving 2 years from 29% to 43%3 - thats as big a step forward as adding temozolomide was in 2005.. Whats the magic? TTF subjects tumor cells to rapidly alternating electrical fields, disrupting cell division. And since its uncontrolled cell division that makes a cell cancerous in the first place, the TTF approach hits the cancer right where it hurts.. TTF doesnt cause nausea, or fatigue, or infections, or low blood counts. It doesnt even require patients come into the office for treatment- but there is a down ...
Everolimus, Temozolomide, and Radiation Therapy in Treating Patients With Newly Diagnosed Glioblastoma This study is ongoing, but not recruiting participants….
The purpose of this study is to treat metastatic melanoma with a combination of standard chemotherapy (decitabine and Temozolomide in a dose escalation
Hancock, E J. and Kilburn, D G., "The effects of cyclophosphamide on in vitro cytotoxic responses to a syngeneic tumour." (1982). Subject Strain Bibliography 1982. 988 ...
THE STUDYS invited discussant, Jordi Bruix, MD, PhD, of the University of Barcelona, Spain, said one of the benefits of the TACTICS study was to evaluate the use of the new unTACEable-based endpoint, which he favors. "The endpoint used in the trial is a good attempt to do something new that may.... ...
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Melphalan is a DNA alkylating agent; induces cytotoxicity through the formation of stable interstrand and intrastrand crosslinks within DNA which inhibits growth of PC-3 cells (IC50 values are 0.074 and 0.77 μM for sequential dosing and single dosing respectively). Learn More ...
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DI-fusion, le Dépôt institutionnel numérique de lULB, est loutil de référencementde la production scientifique de lULB.Linterface de recherche DI-fusion permet de consulter les publications des chercheurs de lULB et les thèses qui y ont été défendues.
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TMZ has obtained the 911 call that was made after Nate Dogg -- cousin of Snoop Dogg -- suffered what was described as a heart attack ... and youre not…