Disease relevance of AIDS106597

• Patterns of cross-resistance to the antifolate drugs trimetrexate, metoprine, homofolate, and CB3717 in human lymphoma and osteosarcoma cells resistant to methotrexate [1].
• The poor solubility of the thymidylate synthase (TS) inhibiting antifolate 10-propargyl-5,8-dideazafolic acid has posed problems for its clinical use and is probably responsible for its renal toxicity [2].
• We have solved crystal structures of two complexes with Escherichia coli thymidylate synthase (TS) bound either to the cofactor analog N10-propargyl-5,8-dideazafolate (CB3717) or to a tighter binding polygutamyl derivative of CB3717 [3].
• A spin-label was attached to the C-terminal side chain of Lactobacillus casei thymidylate synthase (TS, EC2.1.1.45), and EPR spectroscopy was used to study the change in conformational equilibrium that occurs when the enzyme binds nucleotides or the methylenetetrahydrofolate analog CB3717 [4].
• Phase II study of the thymidylate synthetase inhibitor CB3717 (N10-propargyl-5,8-dideazafolic acid) in colorectal cancer [5].

High impact information on AIDS106597

• Similar patterns were seen in this line upon treatment with CB3717 or aphidicolin, indicating that this fragmentation pattern is not specific to TS inhibition and may be characteristic of a more general response than that seen in the other two cell lines [6].
• The same drug sensitivity profile was observed for KB cells, with the exception that these cells were also sensitive to growth inhibition by CB3717 but only in folate-conditioned medium [7].
• Similar results were obtained using two quinazoline-based inhibitors of thymidylate synthase, N10-propargyl-5,8-dideazafolic acid (CB3717) and ICI M247496 [8].
• Trimetrexate (TMTX), 5,10-dideazatetrahydrofolate (DDATHF), and 10-propargyl-5,8-dideazafolate (PDDF, CB3717) are antifolates whose primary intracellular targets are dihydrofolate reductase, glycinamide ribonucleotide formyltransferase, and thymidylate synthase, respectively [9].
• This high sensitivity was related to a high affinity of the FBP for CB3717 and ICI-198,583 (Kd 2-3 nM), which is only 3-fold lower than for folic acid (Kd 1 nM) but significantly higher than for MTX (Kd 100 nM) [10].

Chemical compound and disease context of AIDS106597

• Elimination of salvageable thymidine by the use of dialysed serum also enhanced CB3717 toxicity [11].
• Dipyridamole could exacerbate the nucleotide pool imbalance caused by CB3717, thereby potentiating its toxicity [11].
• The efficacy of 5-fluorouracil in human colorectal cancer is not enhanced by thymidylate synthetase inhibition with CB3717 (N10-propargyl-5,8 dideazafolic acid) [12].
• ICI D1694 has been shown to be a more active anticancer agent than CB3717 in model systems, and it is devoid of the acute renal toxicity associated with the administration of the latter drug to mice [13].

Biological context of AIDS106597

• Finally, the structure shows a unique conformation for the cofactor analog, CB3717, which has implications for structure-based drug design and sheds light on the controversy surrounding the previously observed enzymatic nonidentity between the chemically identical monomers of the TS dimer [14].
• The second crystals contained both dUMP and CB3717 in the active site, but Glu 126 formed three hydrogen bonds to nearby residues (two through water) and was in a position that partially overlapped with the normal phosphate binding site, resulting in a approximately 1 A shift in the phosphate group [15].
• Treatment of cells for 16 hr at an IC50 concentration of CB3717 caused a decrease of 88% in cellular dTTP and a 2,300% increase in dUMP [16].
• In contrast, levels of CB3717 tetra and pentaglutamates declined solely due to dilution during cell division [17].
• To assess these effects, and further define the time course and dose relationship of CB3717-induced renal damage, an assay of glomerular filtration rate (GFR) has been developed which can be used in mice and hence in the screening of novel compounds [18].

Anatomical context of AIDS106597

• These results suggest that CB3717 may be a useful new therapeutic agent in human primary liver cell carcinoma and that blocking the salvage pathway may further increase efficacy [19].
• In addition to CB3717, a metabolite was detected in the feces which comprised 8% of the dose administered [20].

Associations of AIDS106597 with other chemical compounds

• Growth-inhibition studies identified a series of drugs that were preferentially transported via RFC (2,4-diamino structures) or mFBP (CB3717, 2-NH-ZD1694, or 5,8-dideazaisofolic acid), whereas other drugs were efficiently transported via both transport pathways (e.g., DDATHF, ZD1694, BW1843U89, or LY231514) [21].
• It was observed that RFC exhibited an efficient substrate affinity for all analogues except CB3717, 2-NH2-ZD1694, and glutamate side-chain-modified FPGS inhibitors [21].
• Modifications to the bicyclic ring system of the potent thymidylate synthase (TS) inhibitor N-[4-[N-[(2-amino-3,4-dihydro-4-oxo-6- quinazolinyl)methyl]-N-prop-2-ynylamino]benzoyl]-L-glutamic acid (1, CB3717) have led to the synthesis of a series of quinoline antifolates bearing a variety of substituents at the C2 and C4 positions [22].
• The cocrystal structure of TS from Pneumocystis carinii (PcTS), a new drug target for an important pathogen, with its substrate, deoxyuridine monophosphate (dUMP), and a cofactor mimic, CB3717, was determined [23].
• In five pairs of acquired cisplatin-resistant human tumour cell lines (three ovarian, one cervical and one testicular) which encompass all of the main known mechanisms of platinum drug resistance, ZD1694, CB3717 and the DHFR inhibitor, methotrexate, all exhibited non-cross-resistance [24].

Gene context of AIDS106597

• The highly MTX-resistant RAJI/MTX-R and WI-L2/m4 cells showed minor cross-resistance to the dual inhibitor of thymidylate synthetase and DHFR, CB3717 (5- and 15-fold, respectively) [1].
• Compounds with increased selectivity for TS followed with the highly specific inhibitor, CB3717 being synthesised in 1979 at the Institute of Cancer Research (ICR) [25].
• MOLT-3/TMQ200 cells displayed classical multidrug resistance; sequential development of CB3717 resistance in the TMQ-resistant cells resulted in an enhancement of the multidrug-resistance phenotype and a concomitant increase of MDR1 mRNA [26].
• Increased thymidylate synthase in L1210 cells possessing acquired resistance to N10-propargyl-5,8-dideazafolic acid (CB3717): development, characterization, and cross-resistance studies [27].
• However, a membrane-associated folate-binding protein (FBP) offers another route for entry of CB3717 and ICI-198,583 [10].

Analytical, diagnostic and therapeutic context of AIDS106597

• Measurement of intracellular deoxyuridine triphosphate (dUTP) pools, by sensitive radioimmunoassay, demonstrated a large increase in response to CB3717, in a dose- and time-related manner, and this accumulation was enhanced by coincubation with DP [28].
• Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. A phase II study [29].
• CB3717 polyglutamates were measured by HPLC using high specific activity 3H-CB3717 [17].
• Cell culture experiments showed that the ID50 for the cell lines fell within the range of serum CB3717 concentration achieved by a dose of 300 mg m-2 given to patients [19].
• During chemotherapy either with CB3717 or VP16 the serum B12 rose dramatically, in one case reaching levels ten times the upper limit of normal [30].

References