Gene/Protein Disease Symptom Drug Enzyme Compound
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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of chemotherapy in the treatment of early and advanced non-small-cell lung cancer (NSCLC) has increased during the past decade. One of the main reasons for the increased acceptance of chemotherapy is the development of several new cytotoxic agents with a unique mechanism(s) of action and high single-agent activity, combined with a favorable toxicity profile. Pemetrexed (Alimta) is a novel antifolate that inhibits several enzymes involved in DNA synthesis (thymidylate synthase [TS], dihydrofolate reductase [DHFR], and glycinamide ribonucleotideformyltransferase [GARFT]). Pemetrexed's toxicity is markedly reduced by folic acid and vitamin B12 supplementation. The compound has been studied extensively in various tumor types, including NSCLC. In NSCLC, pemetrexed at 500 mg/m2, every 3 weeks, given i.v. over 10 minutes, has shown promising activity, and can safely be administrated with vitamin supplementation. After registration, single-agent pemetrexed will certainly add to the chemotherapeutic options available for pretreated patients and will most likely change significantly chemotherapy prescriptions in second-line chemotherapy. In first-line chemotherapy, the role of platinum-based and -free combination doublet chemotherapy with pemetrexed still needs to be defined. Phase II data indicate high efficacy combined with favorable toxicity for pemetrexed in combination with cisplatin, carboplatin (Paraplatin), oxaliplatin (Eloxatin), gemcitabine (Gemzar), and vinorelbine (Navelbine). This review summarizes the clinical experience obtained thus far during the early clinical development of pemetrexed in NSCLC.
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PMID:Pemetrexed: its promise in treating non-small-cell lung cancer. 1533 59

High local recurrence rates within the previous tumor bed or at the peritoneum remain an unsolved problem after surgical resection of malignant gastrointestinal tumors such as gastric, colorectal or pancreatic carcinoma. Currently, there are no standardized treatment protocols available for the prevention or treatment of peritoneal carcinomatosis. In a basic experimental trial, mitomycin, cisplatin, 5-FU, oxaliplatin and CPT-11 were used to prevent or treat peritoneal carcinomatosis induced in rats. Experiments were performed in three groups (n = 8 each) of animals plus two control groups. In the first group, Mitomycin, Cisplatin, 5-FU, Oxaliplatin and CPT-11 (n = 24 each) were applied directly following tumor cell implantation into the peritoneal cavity. In the second group, early postoperative intraperitoneal (i. p.) chemotherapy (day [d] 5, 10, 15 following surgical intervention for tumor cell transfer) was administered, whereas in the third group, late i. p. chemotherapy (d 15, 20, 25 following surgery) was given via a port-a-cath aiming for significant reduction of a visible, already established peritoneal carcinomatosis. Mitomycin and cisplatin were highly effective to prevent peritoneal carcinomatosis (direct application immediately after tumor cell transfer - 1 (st) treatment group). Using early postoperative i. p. chemotherapy (2 (nd) group), 5-FU and CPT-11 were shown to be significantly effective to reduce the intraperitoneal tumor spread. None of the cytostatic agents was able to decrease significantly an already generated peritoneal carcinomatosis (3 (rd) treatment group). The results suggest that novel chemotherapeutic drugs should be proven for their potential to alter peritoneal metastases of GI tumors i) in comparison with established drugs and ii) depending on the application time and mode.
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PMID:[Five cytostatic substances in animal studies for prevention and treatment of experimentally induced peritoneal carcinomatosis]. 1535 58

Colorectal Cancer is one of the leading causes for cancer related death in the industrialized world. The 5 year overall survival is only 50 - 60 %, although 70 - 80% of the patients are potentially cured by surgical resection. During the last 10 years intensive clinical studies helped to establish the value of adjuvant therapy for colorectal cancer. The introduction of new chemotherapeutic agents like Irinotecan and Oxaliplatin, has led to a significant increase in tumor response and median survival in patients with colorectal carcinoma receiving adjuvant or palliative chemotherapy. In the later situation the sequential application of new combination therapies enables an overall survival of exceeding more than 20 month. In addition the targeted manipulation of molecular tumor mechanisms with new substances like monoclonal antibodies against the epidermal growth factor receptor or the vascular endothelial growth factor shows promising effects. Besides the encouraging improvement of treatment results the introduction of the new drugs has also led to more complexity within choice, strategy and conduction of specific therapies. This manuscript introduces actual treatment concepts and their impact on colorectal cancer.
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PMID:[Colorectal cancer: current treatment options]. 1559 65

A phase II study was designed to evaluate the efficacy and safety of oxaliplatin as second-line treatment in patients with locally advanced or metastatic pancreatic cancer. Eighteen patients with advanced pancreatic cancer previously treated with gemcitabine-based chemotherapy, received oxaliplatin 130 mg/m2 i.v. every 21 days. Patients were treated until tumor progression or unacceptable toxicity. No objective response was observed among the 18 treated patients. Three (16.7%) patients had stable disease for > 2 months. A clinical benefit response was observed in five (27.7%) patients. Toxicity was mild. Oxaliplatin as second-line treatment for patients with unresectable pancreatic cancer is well tolerated and associated with improvement of tumor-related symptoms despite its failure to induce objective responses. LOHP merits further investigation in combination with other drugs as palliative treatment of pretreated patients with advanced pancreatic cancer.
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PMID:Oxaliplatin for pretreated patients with advanced or metastatic pancreatic cancer: a multicenter phase II study. 1577 62

Fluorouracil (FU) has been the mainstay of treatment for metastatic colorectal cancer (mCRC) for many years. However, in recent years, newer chemotherapeutic agents, particularly irinotecan (Campostar; Pfizer Pharmaceuticals, New York, NY, http://www.pfizer.com) and more recently oxaliplatin (Eloxatin; Sanofi-Aventis Inc., New York, NY, http://www.sanofi-aventis.com), have been shown to improve survival in combination with FU-based therapies. These agents were therefore incorporated into first- and second-line treatment strategies. The development of targeted agents that are tumor specific with better toxicity profiles than chemotherapeutic agents has widened the spectrum of therapies for this disease. The U.S. Food and Drug Administration (FDA) recently approved two targeted agents for treating mCRC: an antivascular endothelial growth factor monoclonal antibody (mAb), bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com), in combination with first-line 5-FU-based chemotherapy regimens and the human epidermal growth factor receptor (HER-1/EGFR)-targeted mAb cetuximab (Erbitux; ImClone Systems, Inc., New York, NY, http://www.imclone.com) as monotherapy or in combination with irinotecan as second-line therapy in refractory cancer. These newer, more effective agents are improving clinical outcome for patients with mCRC. However, as the number of agents has increased, choosing the most effective treatment strategy has become increasingly complex. This review discusses the role of the individual agents in the treatment of mCRC and identifies the most effective regimens.
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PMID:Critical evaluation of current treatments in metastatic colorectal cancer. 1582 Dec 45

Oxaliplatin forms a stable 1:1 inclusion complex with cucurbit[7]uril as indicated by NMR, mass spectrometry, isothermal titration calorimetry and X-ray crystallography. The encapsulation of the drug results in a large enhancement in stability, a moderate decrease in reactivity toward guanosine but a much larger decrease in reactivity toward L-methionine, which suggests the encapsulation not only increases the stability of the drug but also may reduce unwanted side effects caused by protein binding of the platinum drug. A preliminary in vitro assay using various tumor cell lines reveals that the encapsulation results in a decrease in the antitumor activity of oxaliplatin.
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PMID:Novel molecular drug carrier: encapsulation of oxaliplatin in cucurbit[7]uril and its effects on stability and reactivity of the drug. 1591 99

Oxaliplatin (L-OHP) is a new third generation 1,2-DACH-platinum derivative. Pre-clinical studies from human cell lines suggested that L-OHP was efficacious in treating advanced or recurrent colorectal cancer. Furthermore, L-OHP and fluorouracil combination was shown to be synergistic both in experimental studies and in clinical trials. Toxicity profiles also differ from other platinum derivatives. Neurotoxicity is much more frequent, but renal toxicity, alopecia, and ototoxicity are less. Combination chemotherapy with L-OHP, infusional 5-fluorouracil, and leucovorin-a treatment regimen known as FOLFOX, has been shown clinical benefit in response rate, time to progression, and overall survival as compared to those achieved with 5-fluorouracil+leucovorin. Thus, introduction of irinotecan and L-OHP into clinical use has been a major advances for patients with metastatic colorectal cancer. Additional research must be required to define optimal dose schedule and sequence of these agents. Inducing remission with first-line treatment has been shown a significant correlation between tumor response and survival (progression free and overall).
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PMID:[Oxaliplatin]. 1612 29

Clinical studies have shown that oxaliplatin, a novel platinum derivative, is a potent chemotherapeutic agent for colorectal cancer when combined with 5-fluorouracil and leucovorin. Although the toxic activity is based on covalent adducts between platinum and DNA, its actual biological behavior is mostly unknown. In an effort to explore the mechanism of tumor susceptibility to oxaliplatin, we examined the cytotoxic effects of oxaliplatin in colorectal cancer cell lines in reference to p53 gene status. Although p53 gene status did not clearly predict sensitivity to oxaliplatin, p53 wild-type cells including HCT116 were sensitive but HCT116 p53-/- were found to be resistant to oxaliplatin. Oxaliplatin caused strong p21waf1/cip1 induction and G0-G1 arrest in p53 wild-type cells, whereas cisplatin did not induce G0-G1 arrest. Assays using p53 wild but p21waf1/cip1 null HCT116 cells revealed that oxaliplatin did not show G0-G1 arrest and reduced growth-inhibitory effects, suggesting that p21waf1/cip1 may be a key element in oxaliplatin-treated p53 wild-type cells. Although HCT116 is DNA mismatch repair-deficient, a mismatch repair-proficient HCT116+ch3 cell line displayed similar responses with regard to p21waf1/cip1-mediated growth inhibition and G0-G1 arrest. In p53 mutant cells, on the other hand, oxaliplatin caused an abrupt transition from G1 to S phase and eventually resulted in G2-M arrest. This abrupt entry into S phase was associated with loss of the p21waf1/cip1 protein via proteasome-mediated degradation. These findings suggest that p21waf1/cip1 plays a role in oxaliplatin-mediated cell cycle and growth control in p53-dependent and -independent pathways.
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PMID:Role of p21waf1/cip1 in effects of oxaliplatin in colorectal cancer cells. 1622 9

Oxaliplatin (L-OHP) was administered to 10 patients previously treated for refractory advanced or recurrent colorectal cancer. The number of times each had received previous chemotherapy treatment ranged from 1 to 5 (median 3) for durations of 2.5 to 52.8 (median 11.7) months. At the time, L-OHP was not yet approved for sale in Japan, and could only be imported from overseas for personal use. As this made it very expensive,we used a low L-OHP dose of 100 mg/body. Combinations with 5-FU were administered differently from previous regimens; these included chronotherapy, weekly high-dose, FOLFOX 4, and FOLFOX 6. L-OHP was administered from 1 to 14 times (median 4.5), and the response to treatment was PR in 2 patients and NC in 5. The response rate was 22.2%. Although in NC there was a tendency toward tumor reduction in 2 of the 5 patients, the treatment had to be suspended because of their financial situations. Overall survival from commencement of the first treatment was 3.1 to 58.7 months (median 17.6+) and after starting L-OHP was 0.6 to 17.2 months (median 6.4+). Adverse events included bone marrow suppression in three patients, 3 cases of leukocytopenia (grade 3 in two patients and grade 4 in one), grade 4 thrombocytopenia in one patient,grade 3 sensory disturbance in one patient,and grade 3 anorexia in two patients. All reactions were able to be controlled except for one patient with Grade 4 thrombocytopenia. In summary,treatment with L-OHP as salvage chemotherapy can possibly contribute to prolongation of survival time in cases of refractory advanced colorectal cancer. It is useful to combine L-OHP with high-dose continuous administration of 5-FU,namely FOLFOX regimens.FOLFOX 6 is the most useful of the FOLFOX regimens because it is simple and can be administered on an outpatient basis.
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PMID:[Clinical administration of oxaliplatin for patients previously treated for refractory advanced or recurrent colorectal cancer]. 1641 Jun 98

Accepted management for colorectal cancer (CRC) involves resection of the primary neoplasm and chemotherapy; the debate continues over the most beneficial order of these components. Preoperative chemotherapy aimed at liver metastases may result in complete pathologic response and replacement of the malignancy with scar. The McGill University liver diseases database was retrospectively reviewed. Forty-one patients receiving treatment between December 2003 and August 2004 were identified, their medical records examined, and liver histology reviewed. The histology of the remnants was linked to the appearance of the lesions on preresection imaging and to the primary colorectal neoplasms. Twenty-seven of the 41 patients (66%) received preoperative chemotherapy (oxaliplatin or irinotecan). Features of the primary neoplasm that predicted resolution of the metastases were absence of tumor budding (P = 0.04), absence of a diffusely infiltrative tumor margin (P = 0.02), and loss of expression of the DNA repair gene O6-methylguanine-DNA methyltransferase (P = 0.08). Oxaliplatin and irinotecan demonstrate beneficial effects in treating hepatic colorectal metastases and should be considered in such patients before resection. We propose the acronym RUMP to denote the remnants of uncertain malignant potential remaining. Further investigation is required to determine any correlation between the drug received and the resulting lesion.
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PMID:Postchemotherapy characteristics of hepatic colorectal metastases: remnants of uncertain malignant potential. 1662 12


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