Disease relevance of ZD 1694

• Raltitrexed, a new drug for advanced colorectal cancer [1].
• An increase in treatment-related deaths was seen on raltitrexed (de Gramont one, Lokich two, raltitrexed 18) due to combined gastrointestinal and haematological toxicity [2].
• Based on these results, we believe a clinical trial of Tomudex in patients with acute myeloid leukemia is warranted [3].
• Combination of raltitrexed and oxaliplatin is an active regimen in malignant mesothelioma: results of a phase II study [4].
• Determinants of activity of the antifolate thymidylate synthase inhibitors Tomudex (ZD1694) and GW1843U89 against mono- and multilayered colon cancer cell lines under folate-restricted conditions [5].

Psychiatry related information on ZD 1694

• However, there may be disincentives within certain national health-care systems to the introduction of a more resource-efficient drug such as raltitrexed [6].
• Toxicity associated with raltitrexed comprised grade 1/2 diarrhoea (31.6% of treatment cycles), nausea (12.4%) and vomiting (8.4%), with no grade 3/4 events; grade 1/2 alopecia (17.9%); grade 1 (only) stomatitis (2.3%) and grade 1/2/3 lethargy (70.3%, only 2.3% grade 3), anaemia (14.3%, only 0.3% grade 3) and neutropenia (3.3%, only 0.3% grade 3) [7].

High impact information on ZD 1694

• Fluorouracil: active in ZD1694 (tomudex)-resistant cell lines with markedly elevated thymidylate synthase levels [8].
• (c) Cell growth inhibition studies with MRP5 transfected HEK293 cells showed that MRP5 conferred high-level resistance (>160-fold) against the antifolates MTX, GW1843, and ZD1694 (raltitrexed) in short-term (4 hours) incubations with high drug concentrations; this resistance was proportional to the MRP5 level [9].
• This suggests that STAT1 regulates expression of gene(s) involved in cell surface trafficking of Fas in response to CPT-11 or tomudex [10].
• Camptothecin-resistant P388/CPT45 cells lacking Top1 are cross-resistant to FdUMP[10] as well as to FdUMP, FdU, and the thymidylate synthase inhibitor raltitrexed (Tomudex) [11].
• PATIENTS AND METHODS: Eligible patients with histologically proven advanced MPM, not pretreated with chemotherapy, WHO performance status (PS) 0 to 2, and adequate hematological, renal, and hepatic function were randomly assigned to receive cisplatin 80 mg/m2 IV on day 1, alone (arm A) or combined with raltitrexed 3 mg/m2 (arm B) [12].

Chemical compound and disease context of ZD 1694

• A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694 [13].
• ZD1694 (Tomudex; Zeneca), a water-soluble, nonnephrotoxic quinazoline, demonstrated activity in colorectal, breast, and pancreatic cancer [14].
• In a panel of 13 nonselected human colon cancer cell lines, we evaluated the role of TS levels in sensitivity to 5-fluorouracil (5FU) and four folate-based TS inhibitors that have been introduced recently into the clinic: ZD1694 (Tomudex, Raltitrexed, TDX), GW1843U89 (GW), LY231514 (LY), and AG337 (Thymitaq, AG) [15].
• CONCLUSIONS: Our data suggest that the combination of oxaliplatin and raltitrexed has substantial antitumour activity in patients with progressive fluoropyrimidine leucovorin + irinotecan pretreated colorectal cancer [16].
• Adding raltitrexed to cisplatin improves overall survival in people with malignant pleural mesothelioma [17].

Biological context of ZD 1694

• These p21waf1-induced cells showed increased sensitivity to doxorubicin, tomudex, and methotrexate as compared to uninduced cells; this condition is associated with increased apoptosis [18].
• ICI D1694 was also a very potent inhibitor of L1210 cell growth (50% inhibitory activity = 8 nM) [19].
• ICI D1694 cured the L1210:ICR ascitic tumor in mice at 0.4 mg/kg daily for 5 days (maximum tolerated dose, approximately 50 mg/kg).(ABSTRACT TRUNCATED AT 400 WORDS)[19]
• DNA damage and p53 induction do not cause ZD1694-induced cell cycle arrest in human colon carcinoma cells [20].
• Treatment of MCF-7 cells with the antifolate tomudex and DNA-damaging agent oxaliplatin also resulted in up-regulation of each of these targets [21].

Anatomical context of ZD 1694

• In contrast, irinotecan (CPT-11) and tomudex sensitized p53 WT, mutant, and null cells to Fas-mediated cell death [10].
• In addition, increased Fas cell surface expression in p53 mutant and null cell lines in response to CPT-11 and tomudex was accompanied by only a slight increase in total Fas mRNA and protein expression, suggesting that these agents trigger p53-independent trafficking of Fas to the plasma membrane [10].
• We have investigated the mechanism of inactivation of thymidylate synthase (TS) by ICI D1694 (a folate-based quinazoline) in normal versus tumor-derived human mammary epithelial cells [22].
• High-titer retroviral packaging cells were generated with OPTecTS and >80% of transduced mouse hematopoietic progenitor cells are resistant to raltitrexed, Thymitaq, and U89 at concentrations that eliminated colony growth of mock-transduced cells [23].
• The transgene was detectable by PCR in transduced bone marrow selected in U89 or raltitrexed, and expression of ecTS from the OPTecTS cDNA in bone marrow exhibited a catalytic rate constant comparable to that of purified recombinant ecTS [23].

Associations of ZD 1694 with other chemical compounds

• Phase I trial of ZD1694, a new folate-based thymidylate synthase inhibitor, in patients with solid tumors [24].
• The L1210:1565 cell line, which has greatly impaired reduced-folate/methotrexate transport and thus is resistant to methotrexate, was significantly cross-resistant to ICI D1694 (121-fold), suggesting that ICI D1694 is dependent on this uptake mechanism for good cytotoxic potency in L1210 cells [19].
• In particular, there is an apparent relatively low affinity for other antifolate inhibitors of dihydrofolate-reductase (MTX, aminopterin, PT523) and thymidylate synthase (ZD1694, ZD9331) [25].
• RESULTS: A total of 844 patients received first-line chemotherapy with various fluorouracil (5-FU)-containing regimens or raltitrexed for advanced disease, and 543 patients were administered adjuvant, protracted venous infusion 5-FU or bolus 5-FU/folinic acid (FA) chemotherapy [26].
• Thymidine phosphorylase moderates thymidine-dependent rescue after exposure to the thymidylate synthase inhibitor ZD1694 (Tomudex) in vitro [27].

Gene context of ZD 1694

• The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent [28].
• Tomudex treatment resulted in the decrease in p27(kip1) expression, with an increase in cyclin E and cdk2 protein expression and kinase activities 24 h after a 2-h exposure [28].
• The increased abundance of hypophosphorylated pRb and binding to transcription factor E2F-1 is consistent with ZD1694-induced cell growth inhibition in HCT-8 cells [29].
• In this study, we have demonstrated the dose- and time-dependent induction of DNA fragmentation accompanied by elevation of p53 and WAF1 protein expression by ZD1694 [29].
• Tomudex belongs to a class of compounds that use the reduced-folate carrier (RFC) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase (FPGS) [30].

Analytical, diagnostic and therapeutic context of ZD 1694

• METHODS: Patients who responded or had stable disease after receiving 12 weeks of the regimens described by de Gramont and Lokich, or raltitrexed chemotherapy, were randomised to either intermittent (a break in chemotherapy, re-starting on the same drug on progression), or continuous chemotherapy until progression [31].
• PATIENTS AND METHODS: From February 1991 to January 1993, 61 patients with a range of solid tumor received 161 courses of ZD1694 given as a single 15-minute intravenous infusion every 3 weeks, at escalating doses from 0.1 to 3.5 mg/m2 [24].
• D-1694-treated cells detached from the dish within 1-2 days after a megaloblastosis, whereas DDATHF-treated cells remained adherent to the dishes for at least 10 days after treatment [32].
• L1210 cells that were incubated for 4 h with 0.1 microM 3H-ICI D1694 accumulated approximately 1.5 microM intracellular 3H, and the high performance liquid chromatography analysis of the cell extracts demonstrated that 96% of the 3H was associated with the ICI D1694 polyglutamate fractions (principally glu4) [19].
• In addition, Tomudex has an acceptable toxicity profile and a convenient dosing schedule (single intravenous injection every 3 weeks) and thus appears to offer real potential as a novel agent for the treatment of patients with advanced CRC [33].

References