Disease relevance of AIDS-096718

• CONCLUSION: The dose-limiting toxicity, MTD, and recommended phase II dose of LY231514 when administered weekly for 4 weeks every 42 days are neutropenia, 40 mg/m2, and 30 mg/m2, respectively [1].
• PURPOSE: To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC) [2].
• In Vitro schedule-dependent interactions between the multitargeted antifolate LY231514 and gemcitabine in human colon adenocarcinoma cell lines [3].
• The scheduling of antifolate antitumor agents, including the new multitargeted autofolate LY231514 (MTA), with 5-fluorouracil was explored in the human MX-1 breast carcinoma and human H460 and Calu-6 non-small cell lung carcinoma xenografts to assess antitumor activity and toxicity (body weight loss) [4].
• Compounds 3a and 3b were more inhibitory than LY231514 against TS from Lactobacillus casei and Escherichia coli [5].

High impact information on AIDS-096718

• Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group [2].
• Cell cycle modulation by a multitargeted antifolate, LY231514, increases the cytotoxicity and antitumor activity of gemcitabine in HT29 colon carcinoma [6].
• Enhancements were also found for combinations of TMTX with the GARFT inhibitors AG2032, Lometrexol, and LY309887, the AICARFT inhibitor AG2009, and the TS inhibitors LY231514 and Tomudex but not with the GARFT inhibitor LL95509 or with the TS inhibitors AG337, ZD9331, and BW1843U89 [7].
• For example, the Ki values of the pentaglutamate of LY231514 are 1.3, 7.2, and 65 nM for inhibition against TS, DHFR, and GARFT, respectively [8].
• Studies with mutant cell lines demonstrated that LY231514 requires polyglutamation and transport via the reduced folate carrier for cytotoxic potency [8].

Chemical compound and disease context of AIDS-096718

• A phase II study of pemetrexed disodium (LY231514) in patients with locally recurrent or metastatic breast cancer [9].
• Pemetrexed (Alimta, MTA, multitargeted antifolate, LY231514) for malignant pleural mesothelioma [10].
• Prevention of thymidine and hypoxanthine rescue from MTA (LY231514) growth inhibition by dipyridamole in human lung cancer cell lines [11].
• We studied the effects of folic acid on modulating the toxicity and antitumor efficacy of LY231514 [12].

Biological context of AIDS-096718

• PURPOSE: To determine the toxicities, maximal-tolerated dose (MTD), pharmacokinetic profile, and potential antitumor activity of LY231514, a novel thymidylate synthase (TS) inhibitor [1].
• The reversal pattern of LY231514 suggests that although TS may be a major site of action for LY231514 at concentrations near the IC50, higher concentrations can lead to inhibition of DHFR and/or other enzymes along the purine de novo pathway [8].
• The metabolic effects exerted by LY231514 on the folate and nucleotide pools are also quite distinct from those of MTX and LY309887 [13].
• The LD50 occurred at 60- and 250-fold lower doses of LY231514 in DBA/2 and CD1 nu/nu mice, respectively, maintained on low folate diet compared to standard diet [12].

Associations of AIDS-096718 with other chemical compounds

• The novel pyrrolopyrimidine-based antifolate LY231514 (MTA), inhibits multiple folate-requiring enzymes including thymidylate synthase, glycinamide ribonucleotide formyltransferase and dihydrofolate reductase [14].
• The objective of this study was to determine the response rate in chemonaive patients with inoperable, locally advanced, recurrent, or metastatic cervical cancer treated with pemetrexed (Alimta, LY231514), a multitargeted antifolate [15].
• Pemetrexed (Alimta, LY231514) demonstrates clinical activity in chemonaive patients with cervical cancer in a phase II single-agent trial [15].
• In cell culture, moderate cross-resistance (about 2-fold) was observed to 1-ss-D-arabinofuranosylcytosine (ara-C), 2-chloro-2'deoxyadenosine (CdA), LY231514 (ALIMTA), and cisplatin (CDDP), and pronounced cross-resistance (>23-fold) to 2',2'-difluorodeoxyuridine (dFdU) and 2',2'-difluorodeoxyguanosine (dFdG) [16].

Gene context of AIDS-096718

• PURPOSE: To examine the activity of glutamyl hydrolase (GH) on the poly-gamma-glutamates of multitargeted antifolate (MTA) (LY231514) and the effect of enhanced GH on the pharmacological activity of MTA [17].
• All synthesized compounds inhibited TS more potently than compound 2 (LY231514), and the C8-ethyl analogue (7) showed a remarkable inhibitory activity against TS (IC50=0.017 microM) [18].
• LY231514 treatment (i.p., qd x 10) significantly delayed tumor growth in the GC3 carcinoma xenograft model [19].
• However, a thymidine kinase-deficient mutant of this same tumor line demonstrated heightened sensitivity to the in vivo antitumor activity of LY231514 with complete regression of established tumors and a large number of tumor-free survivors after one course of treatment [19].

Analytical, diagnostic and therapeutic context of AIDS-096718

• N-[4-[2-(2-amino-3,4-dihydro-4-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl ]-benzoyl]-L-glutamic acid (LY231514) is a novel pyrrolo[2,3-d]pyrimidine-based antifolate currently undergoing extensive Phase II clinical trials [8].
• Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts [4].

References