Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pemetrexed (LY231514) is a new-generation antifolate that, in its polyglutamyl forms, is a potent inhibitor of thymidylate synthase and glycinamide ribonucleotide formyltransferase (GAR transformylase). This study explored the mechanisms of resistance to pemetrexed in L1210 murine leukemia cells using chemical mutagenesis with 5-formyltetrahydrofolate (5-formylTHF) as the growth substrate. A cell line, MTA-13, was identified that was 8.5-fold resistant to pemetrexed with comparable cross-resistance to ZD1694 (Tomudex) and lesser cross-resistance (5-fold) to ZD9331 [(2S)-2-(O-fluoro-p-[N-(2,7-dimethyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-N-(prop-2-ynyl)amino]benzamido)-4-(tetrazol-5-yl)-butyric acid], DDATHF (dideazatetrahydrofolate) (3.5-fold), and methotrexate (MTX) (2.7-fold) but comparable sensitivity to trimetrexate. Influx of pemetrexed, MTX, and 5-formylTHF into MTA-13 cells was decreased by 56, 47, and 38% compared to wild-type cells. Folate receptor expression was negligible in both cell lines. Net drug uptake declined within 15min to a slower, constant rate over the next 45min, reflecting the rate of accumulation of pemetrexed polyglutamate derivatives. This rate in the MTA-13 line was half that of the wild-type cells. Accumulation of 50nM [3H]pemetrexed, 25nM [3H]5-formylTHF, or 50nM [3H]DDATHF after 3 days was decreased to 35, 46, and 56% the level of L1210 cells. The reduced folate carrier (RFC) message and protein were decreased by 50%, and folypolyglutamate synthetase (FPGS) message was decreased by 65% in MTA-13 cells. No mutations were detected in either protein by DNA sequence analysis. There was a slight decrease (approximately 25%) in thymidylate synthase mRNA, without mutations in the protein, and there was no change in GAR transformylase message. The data indicate that resistance to pemetrexed in the MTA-13 cell line was due to changes in both RFC and FPGS expression, two proteins that act in tandem to regulate polyglutamation of folates and antifolates in cells, resulting in cellular depletion of these active pemetrexed congeners.
 ...
PMID:Decreased expression of the reduced folate carrier and folypolyglutamate synthetase is the basis for acquired resistance to the pemetrexed antifolate (LY231514) in an L1210 murine leukemia cell line. 1266 51

Multiple myeloma (MM) is a malignancy of terminally differentiated B lymphocytes, characterized by accumulation of a monotypic plasma cell population in the bone marrow, monoclonal immunoglobulin in serum and/or urine and osteolytic lesions. Despite recent advances in the treatment, MM remains an incurable disease. This calls for an effort to develop novel therapeutics in order to eradicate the disease. Here we have evaluated the potential antimyeloma action of Pemetrexed, an antifolate drug that has shown promising results in other neoplastic diseases. Pemetrexed had a potent antimyeloma effect on cell lines sensitive and resistant to conventional therapeutic agents, and was also efficient on fresh cells from patients and in a murine MM model. Furthermore, Pemetrexed abrogated the protective action on MM cell death of several growth factors produced by the bone marrow microenvironment. Mechanistic studies indicated that Pemetrexed provoked this action by a combined effect that included cell cycle blockade, probably by p21 upregulation, and induction of apoptosis through caspase-dependent and -independent mechanisms. These data, together with the fact that Pemetrexed is already licensed for the therapy of other neoplastic diseases, opens the possibility for the inclusion of Pemetrexed in the therapeutic armamentarium to battle MM.
Leukemia 2007 Apr
PMID:Pemetrexed acts as an antimyeloma agent by provoking cell cycle blockade and apoptosis. 1731 26

Pemetrexed (Pem) is a novel antimetabolite type of anticancer drug that demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung carcinoma and malignant pleural mesothelioma. It inhibits enzymes involved in the folate pathway, for which the presence of its free carboxylic groups is necessary. The heteroaromatic ring system of Pem has a modifiable amino group, which opens a possibility to apply a new strategy to conjugate Pem to carrier molecules. Considering this as well as the necessity of untouched carboxylic groups of Pem in the new conjugates, we developed a new synthesis strategy. Here, we describe the synthesis and the characterization of new Pem-peptide conjugates in which cell-penetrating octaarginine or/and lung-targeting H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH(2) peptide is attached to the drug by thioether bond. The conjugates characterized by RP-HPLC and MS exhibited cytostatic effect in vitro on non-small cell lung carcinoma as well as on human leukemia cell lines. The IC(50) values of the conjugates were similar, but the conjugates with H-Ile-Glu-Leu-Leu-Gln-Ala-Arg-NH(2) sequence were slightly more effective. Our data show that the in vitro cytostatic effect of the free Pem was essentially maintained after conjugation with cell-penetrating or cell-targeting peptides. Thus, the conjugation strategy reported could lead to the development of a new generation of active Pem conjugates.
 ...
PMID:New pemetrexed-peptide conjugates: synthesis, characterization and in vitro cytostatic effect on non-small cell lung carcinoma (NCI-H358) and human leukemia (HL-60) cells. 2207 54

Pemetrexed, a folate antimetabolite, combined with cisplatin is used as a first-line therapy for malignant pleural mesothelioma (MPM) and locally advanced or metastatic non-small-cell lung cancer (NSCLC). Pemetrexed arrests cell cycle by inhibiting three enzymes in purine and pyrimidine synthesis that are necessary for DNA synthesis. Pemetrexed also promotes apoptosis in target cells, but little is known about its mechanism in cancer cells. We have previously shown that pemetrexed can result in endoplasmic reticulum (ER) stress, and it can lead to downstream apoptosis. In this study, we further elucidate this mechanism. Our data show that pemetrexed increases Noxa expression through activating transcription factor 4 (ATF4) and activating transcription factor 3 (ATF3) upregulation. Furthermore, pemetrexed induces apoptosis by activating the Noxa-Usp9x-Mcl-1 pathway. Inhibition of Noxa by small interfering RNA (siRNA) promotes Usp9x (ubiquitin-specific peptidase 9, X-linked) expression. Moreover, downregulation of the deubiquitinase Usp9x by pemetrexed results in downstream reduction of myeloid cell leukemia 1 (Mcl-1) expression. Mechanistically, Noxa upregulation likely reduces the availability of Usp9x to Mcl-1, thereby promoting its ubiquitination and degradation, leading to the apoptosis of neoplastic cells. Thus, our findings demonstrate that Noxa-Usp9x-Mcl-1 axis may contribute to pemetrexed-induced apoptosis in human lung cancer cells.
...
PMID:Usp9x- and Noxa-mediated Mcl-1 downregulation contributes to pemetrexed-induced apoptosis in human non-small-cell lung cancer cells. 2499 68