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 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The search for new combination chemotherapeutic regimens for the treatment of non-small-cell lung cancer is motivated not only by the desire to increase the objective tumor response and survival rates, but also by the desire to reduce toxicity, decrease symptoms, and improve the psychological well-being of treated patients. At present, the overall phase II response rates with existing combination chemotherapeutic regimens are approximately 15% to 30%, and the median survival rates are about 8 to 9 months. The median 1-year survival rates are about 30% to 40%, while the 2-year survival rates are only about 10% to 15%. Thus, while we have made substantial progress in the treatment of this disease, the long-term outcome is still relatively bleak. This article reviews the results of a phase I trial with a new combination chemotherapeutic regimen (gemcitabine [Gemzar] and the novel antifolate, Alimta), and outlines the rationale for, and design of, an ongoing phase II trial.
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PMID:Gemcitabine/Alimta in locally advanced or metastatic non-small-cell lung cancer. 1096 Sep 46

The activity of antimetabolite inhibitors of de novo deoxyribonucleotide biosynthesis can be compromised by the salvage of extracellular preformed nucleosides and nucleobases. Dipyridamole (DP) is a nucleoside transport inhibitor that has been used clinically in an attempt to increase antimetabolite activity; however, DP binds tightly to the serum protein alpha1-acid glycoprotein (AGP) thereby rendering this therapeutic strategy largely ineffective. Four novel DP analogues (NU3076, NU3084, NU3108, and NU3121) have been developed with substitutions at the 2,6- and 4,8-positions of the pyrimidopyrimidine ring. The novel DP analogues inhibit thymidine (dThd) uptake into L1210 cells in vitro (NU3076 IC(50), 0.25 microM; NU3084 IC(50), 0.27 microM; NU3108 IC(50), 0.31 microM; NU3121 IC(50), 0.26 microM; and DP IC(50), 0.37 microM), but, unlike DP, their activity remains largely unaffected in the presence of 5 mg/ml AGP. The four DP analogues inhibit dThd and hypoxanthine rescue from Alimta (multitargeted antifolate)-induced growth inhibition in A549 and COR L23 human lung carcinoma cell lines in the presence of 2.5 mg/ml AGP, whereas the activity of DP is completely abolished. i.p. administration of 10 mg/kg NU3108, NU3121, and DP produced peak plasma concentrations of 4.4, 2.1, and 6.7 microM, respectively, and levels were sustained above 1 microM for approximately 45 min (DP) and 120 min (NU3108 and NU3121). [3H]thymidine incorporation into COR L23 xenografts grown in CD1 nude mice was reduced by 64% (NU3108), 44% (NU3121), and 65% (DP) 2 h after administration of the nucleoside transport inhibitors. In conclusion, two novel DP analogues (NU3108 and NU3121) have been identified that do not bind to AGP and that display superior pharmacokinetic profiles in comparison to DP and inhibit [3H]thymidine incorporation into human tumor xenografts in vivo.
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PMID:In vitro and in vivo properties of novel nucleoside transport inhibitors with improved pharmacological properties that potentiate antifolate activity. 1144 30

The impact of p53 status on cellular sensitivity to antifolate drugs has been examined in seven human cell lines (A549, MCF7, T-47D, CCRF-CEM, COR-L23, A2780, and HCT-116) and p53 nonfunctional counterparts of two of the cell lines (HCT-116/N7 and A2780/CP70). p53 status was determined by sequencing and functional assays. The sensitivities of the cell lines to growth inhibition (sulphorhodamine B assay) produced by four antifolate drugs (Alimta, methotrexate, raltitrexed, and lometrexol) were studied. There was no clear relationship between functional p53 status and sensitivity to methotrexate or lometrexol, whereas a functional p53 status was possibly associated with resistance to Alimta- and raltitrexed-induced growth inhibition. In contrast, in the two pairs of related human tumor cell lines (HCT-116 and HCT-116/N7 and A2780 and A2780/CP70) cells with functional p53 were more sensitive to Alimta- and raltitrexed-induced growth inhibition (P = 0.002). Detailed studies were performed with the A2780 cell lines, and in the parental cells sensitivity to Alimta- and raltitrexed-induced cytotoxicity (clonogenic assay) was similar to the sensitivity determined in the sulphorhodamine B assay. However, in A2780/CP70 cells, 1 microM of drug resulted in only 40-60% growth inhibition yet > or = 85% cytotoxicity. After Alimta and raltitrexed exposure for < or = 72 h, there were no differences between the A2780 and A278/CP70 cell lines in cell cycle phase distribution, absolute cell number, or the induction of apoptosis. However, the cellular protein content of the A2780/CP70 cells was 3-6-fold higher than in A2780 cells after Alimta and raltitrexed treatment, suggesting that cells without functional p53 can maintain protein synthesis in the absence of cell division (unbalanced cell growth). In conclusion, the apparent impact of functional p53 status on sensitivity to antifolate drugs may depend upon the phenotypic/genotypic background as well as the assay used to measure cellular sensitivity.
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PMID:The impact of p53 status on cellular sensitivity to antifolate drugs. 1144 31

Alimta is a new-generation antifolate with inhibitory activity against multiple enzymes, including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase. Alimta is undergoing broad phase II evaluation as a single agent, and preliminary results show responses in several tumor types, including breast carcinoma. Doxorubicin is often used in combination chemotherapy of breast cancer. Because the two drugs have mechanisms of action that might be complementary, we investigated a possible synergism between doxorubicin and Alimta on growth inhibition of ZR-75-1 human breast carcinoma cells. Cytostatic activity was evaluated using semi-automated MTT assays, and drug interactions were determined using CalcuSyn (Chou/Hayball) multiple drug effect analyses. The cells were exposed to Alimta or doxorubicin as single agents and combinations for 24 hours starting at the time of plating or for 72 hours starting 24 hours after plating with a total culture time of 96 hours. Preincubation with Alimta for 24 hours followed by exposure to doxorubicin for 72 hours resulted in highly synergistic activity, whereas the opposite sequence or simultaneous exposure produced mainly an additive response. DNA flow cytometry studies indicated that Alimta causes a build-up of cells near the G1/S interface after 24 hours of incubation. The data suggest that, to obtain maximal antitumor activity, Alimta should precede doxorubicin when the drugs are given in combination chemotherapy protocols.
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PMID:Sequence dependence of Alimta (LY231514, MTA) combined with doxorubicin in ZR-75-1 human breast carcinoma cells. 1184 74

The maximum tolerated dose of the multitargeted antifolate drug pemetrexed is 600 mg/m(2) every 3 weeks in heavily pretreated patients without folic acid supplementation. However, with folic acid supplementation, higher doses have been given without limiting side effects. The dose-limiting toxicities of pemetrexed are neutropenia, asthenia, and thrombocytopenia. Other adverse effects include anemia, anorexia, rash, nausea, vomiting, peripheral edema, diarrhea, mucositis, and reversible elevations of transaminase and creatinine levels. Multiple pemetrexed combination phase I trials have been completed or are underway. Without folic acid supplementation, pemetrexed doses of 400 to 600 mg/m(2)could be safely administered with full therapeutic doses of irinotecan, gemcitabine, cisplatin, carboplatin, oxaliplatin, and 5-fluorouracil. Preliminary data from other ongoing trials (with folic acid and vitamin B(12) supplementation) have similarly shown that pemetrexed doses of at least 400 to 500 mg/m(2) can be safely administered with therapeutic doses of vinorelbine, docetaxel, and paclitaxel. Combination studies of pemetrexed with agents active in breast cancer (doxorubicin, epirubicin, and cyclophosphamide) and chest radiotherapy are also now underway. Adverse effects of these combinations have included neutropenia, anemia, thrombocytopenia, asthenia, vomiting, diarrhea, rash, nausea, anorexia, mucositis, and reversible transaminase elevation. The phase I trials of pemetrexed have consistently shown activity against a broad range of tumor types, including colorectal cancer, pancreatic cancer, breast cancer, non-small cell lung cancer, and mesothelioma. This activity has been noted not only in the combination trials, but when pemetrexed is given as a single agent as well. Pemetrexed is a promising drug. It is active against a broad range of cancers, and it has manageable side effects that seem to be lessened with folic acid and vitamin B(12) supplementation.
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PMID:Phase I trials of pemetrexed. 1202 87

The novel agent pemetrexed inhibits thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Significant activity has been seen in completed phase II trials of pemetrexed in non-small cell lung cancer and breast cancer. Pemetrexed is also active in combination with other agents such as gemcitabine, cisplatin, and carboplatin. In addition, this agent shows promising activity in bladder, head and neck, esophageal, renal, and cervical carcinomas. Preliminary results of studies in these tumor types are reviewed.
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PMID:Pemetrexed in the treatment of selected solid tumors. 1202 93

Pemetrexed is a novel antifolate effective in the treatment of mesothelioma. Studies were undertaken to characterize the transport of this antifolate in this tumor. We report the presence of a novel, concentrative high-affinity transport activity in three human mesothelioma cell lines, characterized in detail in the NCI-H28 line, with a pemetrexed influx K(t) of 30 nM and V(max) of 10 nmol/g protein/min. This route is highly specific for pemetrexed, with a substrate specificity pattern quite different from that of the reduced folate carrier and folate receptors. In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331). Besides its impact on the transport of pemetrexed, this high-affinity route may represent another pathway by which physiological folates are transported into human cells.
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PMID:A novel folate transport activity in human mesothelioma cell lines with high affinity and specificity for the new-generation antifolate, pemetrexed. 1243 30

Thymidylate synthase (TS) is a key enzyme in the synthesis of 2'-deoxythymidine-5'-monophosphate, an essential precursor for DNA biosynthesis. For this reason, this enzyme is a critical target in cancer chemotherapy. As the first TS inhibitor in clinical use, 5-fluorouracil (5-FU) remains widely used for the treatment of colorectal, pancreatic, breast, head and neck, gastric, and ovarian cancers. The reduced folate, leucovorin, has been shown to enhance the activity of 5-FU in colorectal cancer. However, response rates of the combination remain in the 25%-30% range, and much effort has been focused on designing new, more potent TS inhibitors. Raltitrexed is a folate analogue that is approved as first-line therapy for advanced colorectal cancer in Europe, Australia, Canada, and Japan, although it remains an investigational agent in the United States. Pemetrexed is an antifolate analogue that has shown promising activity in several solid tumor types, including mesothelioma. ZD9331, a highly specific TS inhibitor that dose not require polyglutamation for its activation, has shown activity in patients with refractory ovarian and colorectal cancer. Capecitabine is an oral fluoropyrimidine carbamate that was designed to generate 5-FU preferentially in tumor cells; this agent was recently approved by the US Food and Drug Administration as first-line therapy for patients with advanced colorectal cancer. As the number of TS inhibitors available for general clinical use increases, further research is needed to elucidate the critical molecular and biochemical elements that determine the efficacy and tumor specificity of each compound.
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PMID:Thymidylate synthase: a critical target for cancer chemotherapy. 1245 Apr 20

Pemetrexed is a novel antifolate that inhibits three enzymes in the de novo purine and pyrimidine pathways including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It becomes highly polyglutamated once inside cancer cells, resulting in prolonged intracellular retention and 60-fold greater inhibition of thymidylate synthase than the monoglutamated form. Several phase II and III studies have shown that pemetrexed has significant antitumor activity against a variety of tumor types including mesothelioma, non-small cell lung cancer, and colon, pancreatic, and breast cancers. Pemetrexed appears to provide non-cross-resistant cytotoxic activity against breast cancers that have been treated with anthracyclines, taxanes, and capecitabine. Preclinical studies have suggested that pemetrexed enhances the cytotoxicity of several other important chemotherapeutic agents active against breast cancer including doxorubicin, paclitaxel, cisplatin, and gemcitabine. In vitro studies have shown that pemetrexed treatment synchronizes cancer cells at the G(2)/S interphase, leading to synchronous entry into S phase. Ongoing phase II studies of pemetrexed combinations in breast cancer hope to exploit the cell cycle modulatory effects of this drug as well as its excellent tolerability.
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PMID:Pemetrexed: an active new agent for breast cancer. 1257 13

Pemetrexed is a novel multitargeted antifolate analog. The drug has shown encouraging activity in a wide range of solid tumors, including cervix, head and neck, and bladder carcinomas, which are the focus of this review. Toxicity, particularly hematologic, is higher in patients with these tumor types than in other populations exposed to pemetrexed. Supplementation with folic acid and vitamin B(12) appears to effectively reduce the incidence of severe toxicity and may optimize the therapeutic index of pemetrexed in patient subsets with poor nutritional status. The role of this agent in the management of these and other tumor types, as a single agent or in combination, shall be determined by randomized phase III studies.
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PMID:Pemetrexed in bladder, head and neck, and cervical cancers. 1257 15


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