Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dipyridamole (DPD) has been shown to inhibit the motility of cells in culture. We have tested the effect of DPD on the invasion in confronting organ culture of the following malignant cell lines: mouse MO4 cells; rat NBT II bladder tumor cells; human SA4 glioblastoma cells; mouse LLC H61 lung carcinoma cells; and mouse F87 C1.6T2 melanoma x lymphocyte hybrid cells. At concentrations of 20 micrograms/ml or higher, DPD inhibited the invasion of all cell types into embryonic chick heart. In serum-free culture medium the anti-invasive concentration of DPD was about ten times lower. Anti-invasive concentrations of DPD also inhibited proliferation of the malignant cells. Both inhibition of invasion and of proliferation were reversible.
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PMID:Effect of dipyridamole on invasion of five types of malignant cells in organ culture. 277 69

A potent quinazoline antifolate inhibitor of thymidylate synthase, CB3717, inhibits the growth of A549 human lung carcinoma cells: ID50 2.74 +/- 0.53 microM. The toxic effects of thymidylate synthase inhibition may be prevented by salvage of exogenous thymidine. The nucleoside transport inhibitor, dipyridamole, at the non-toxic concentration of 1 microM, inhibited [3H]thymidine uptake/incorporation by more than 95% and significantly reduced the ID50 of CB3717 to 0.98 +/- 0.28 microM. Elimination of salvageable thymidine by the use of dialysed serum also enhanced CB3717 toxicity. Since dipyridamole was equally effective in the presence or absence of dialysed serum and was more effective than dialysed serum alone, inhibition of nucleoside efflux may be an important aspect of its potentiation. Efflux of [5-3H]deoxyuridine was inhibited by 89% and [3H]thymidine efflux by 61% in the presence of 1 microM dipyridamole. Inhibition of thymidylate synthase increases the deoxyuridine nucleotide/thymidine nucleotide pool ratio. Dipyridamole could exacerbate the nucleotide pool imbalance caused by CB3717, thereby potentiating its toxicity.
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PMID:Potentiation of quinazoline antifolate (CB3717) toxicity by dipyridamole in human lung carcinoma, A549, cells. 337 15

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