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A L Jackman - One of the best experts on this subject based on the ideXlab platform.
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a phase i trial of zd9331 a water soluble nonpolyglutamatable Thymidylate Synthase Inhibitor
Clinical Cancer Research, 2003Co-Authors: Ruth Plummer, Charlotte Rees, Andrew Hughes, Philip Beale, Martin Highley, Jose Manuel Trigo, Sathyarathnarn Gokul, I Judson, H Calvert, A L JackmanAbstract:Purpose: ZD9331 is a novel, direct-acting antifolate cytotoxic that does not require polyglutamation for activity, and is a specific Thymidylate Synthase Inhibitor. This Phase I trial aimed to determine the maximum tolerated dose of ZD9331, given as a 30-min i.v. infusion on days 1 and 8 of a 21-day cycle. Pharmacokinetic parameters and tumor response were also assessed. Experimental Design: A total of 71 patients, with a range of solid malignancies and refractory to standard therapies (44% had received ≥3 prior chemotherapy regimens), were treated. The most common malignancies were colorectal cancer (35% of patients) and ovarian cancer (31%). ZD9331 was escalated from 4.8 mg/m 2 /day. Results: Dose-limiting toxicity occurred at 162.5 mg/m 2 ZD9331, with grade 4 thrombocytopenia, grade 4 neutropenia lasting ≥7 days, and grade 3 nonhematologic toxicity. Plasma clearance of ZD9331 was slow and dose-dependent; however, ZD9331 pharmacokinetics were nonlinear. Pharmacodynamics of ZD9331 were determined by measurement of plasma deoxyuridine, which increased at all of the dose levels; dose-related increases in plasma deoxyuridine were significant ( P = 0.003) on day 5. Stable disease was observed in 37% of patients; 23% of ovarian cancer patients had a ≥50% reduction in CA125 levels. Conclusions: The maximum tolerated dose of this schedule was 130 mg/m 2 . The toxicity profile at this dose was acceptable, with 7 of 28 patients treated developing grade 3/4 neutropenia and thrombocytopenia, 2 grade 4 diarrhea, and 2 grade 3/4 rash. This schedule was convenient and demonstrated activity in extensively pretreated patients; therefore, this is the recommended dose for study in Phase II trials.
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a rationale for the clinical development of the Thymidylate Synthase Inhibitor zd9331 in ovarian and other solid tumours
Biochimica et Biophysica Acta, 2002Co-Authors: A L Jackman, Davinder S Theti, R Kimbell, L Brunton, Camille Melin, Wynne G Aherne, Michael I WaltonAbstract:Abstract ZD9331 is an antifolate drug that potently and specifically inhibits Thymidylate Synthase (TS). In contrast with TS Inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC 50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 ( r =0.50; p =0.097) and raltitrexed ( r =0.74; p =0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 ( r =0.77; p =0.013) and raltitrexed IC 50 ( r =0.84; p =0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC 50 ratios) ( r =0.62; p =0.048). Similarly, cell lines with IC 50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA ( p =0.0087) compared with those with ratios≤median. The four ovarian and one colon cell line that were relatively more sensitive to ZD9331 expressed FPGS mRNA≤median ( p =0.061). Thus, ZD9331 overcomes resistance to raltitrexed in ovarian tumour cell lines expressing low levels of FPGS. These data, and others demonstrating a lack of cross-resistance between cisplatin and ZD9331, support the clinical evaluation of ZD9331 in platinum-refractory ovarian cancer.
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phase i and pharmacologic study of oral zd9331 a novel nonpolyglutamated Thymidylate Synthase Inhibitor in adult patients with solid tumors
Journal of Clinical Oncology, 2002Co-Authors: Maja J A De Jonge, A L Jackman, Andre S T Planting, Robert S Smith, Cornelis J A Punt, Alex Sparreboom, Marlies E W J Peters, Jacqueline Van De Schraaf, Pieter H M De Mulder, J VerweijAbstract:PURPOSE: To assess the toxicity profile and dose-limiting toxicities (DLTs), to determine the maximum-tolerated dose, and to study the pharmacokinetics of ZD9331 when administered orally to patients with advanced solid tumors. PATIENTS AND METHODS: Patients were treated with oral ZD9331 given once daily (od) or twice daily (bid) for 5, 7, or 10 days; cycles were repeated every 21 days at doses ranging from 2.5 to 40 mg. For pharmacokinetic analysis, plasma sampling was performed during the first course and assayed using a validated liquid chromatographic–tandem mass spectrometry assay. Plasma levels of 2′-deoxyuridine were measured as a surrogate marker for TS inhibition. RESULTS: Forty-two patients received a total of 166 courses. The DLTs were myelosuppression and skin rash. Dose escalation of oral ZD9331 from 2.5 to 40 mg, as a single daily dose, resulted in a less than proportional increase in the plasma area under the concentration-time curve of ZD9331. The plasma drug exposure per cycle for the sche...
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raltitrexed tomudextm a highly polyglutamatable antifolate Thymidylate Synthase Inhibitor
1999Co-Authors: Leslie Richard Hughes, T C Stephens, Thomas F Boyle, A L JackmanAbstract:Folic acid has, over the past 50 yr, formed the basis of an enormous amount of medicinal chemistry aimed at finding improved anticancer agents. This stemmed from the discovery of aminopterin (AMT) and methotrexate (MTX) in the late 1940s. Several years after their discovery, they were shown to exert their antitumor activity via the inhibition of dihydrofolate reductase (DHFR). MTX is still widely prescribed today for the treatment of a number of solid tumors and leukemias (see Chapter 3). Over the last decade there has been a resurgence in the number of folic acid analogs entering clinical studies that has resulted from the knowledge that a number of key enzymic reactions in the de novo biosynthesis of nucleotides depend on folate cofactors. The cellular and in vivo pharmacology of MTX and some of its more recent analogs have been very well described in the literature and has formed a platform of knowledge for the development of the antifolate Thymidylate Synthase (TS) Inhibitors over the last 20 yr (see Chapter 1). For example, it was shown that the cytotoxicity induced by the indirect inhibition of TS by MTX may be antagonized by its Inhibitory effects on de novo purine synthesis (1). The antipurine effects of MTX were also believed to contribute to the drug-induced gut toxicity in mice (2). These and other data, particularly that relating to 5-fluorouracil (5FU) metabolism and activity, argued that specific folate-based Inhibitors of TS may prove to be better drugs (3). Furthermore, ground-breaking research on other aspects of MTX action including drug resistance and polyglutamation substantially contributed to the acceleration of the development of TS Inhibitors from basic concept through to clinical evaluation. Indeed several of the early dual Inhibitors of DHFR and TS were 5,8-dideaza (quinazoline) analogs of MTX (see Subheading 2.1.). This chapter focuses on reviewing the medicinal chemistry path from these early compounds to the selection of Tomudex (Raltitrexed; ZD1694; Fig. 1) for clinical study. Additionally, a summary is provided of the current state of knowledge regarding the cellular and in vivo pharmacology of the drug. Readers are also advised of a recent review that may provide more detailed information on certain aspects of development (3).
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent Thymidylate Synthase Inhibitor ZD9331 in mice
Youcef M Rustum - One of the best experts on this subject based on the ideXlab platform.
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characterisation of a synergistic interaction between a Thymidylate Synthase Inhibitor zd1694 and a novel lipophilic topoisomerase i Inhibitor karenitecin bnp1100 mechanisms and clinical implications
European Journal of Cancer, 1999Co-Authors: Seiichi Matsui, W Endo, C Wrzosek, K Haridas, P Seetharamulu, Frederick H Hausheer, Youcef M RustumAbstract:Abstract We developed a combination protocol for Inhibitors of Thymidylate Synthase (TS) and DNA topoisomerase I (Topo I) that can exert highly lethal effects in vitro against HCT-8 human colorectal cancer cells. The specific schedule was constructed so that a TS Inhibitor could induce not only primary DNA damage but also cellular conditions optimal for the efficient action of a Topo I Inhibitor. The initial drug treatment consisted of a brief exposure to a quinazoline-based antifolate, ZD1694. After an interval of approximately one cell-doubling time, cells were exposed for 8–24 h to BNP1100, a Karenitecin-class 7-thiomethyl-camptothecin, in the presence of 1–10 μM thymidine; the latter acted as a crucial factor to promote the collision of moving replication forks with the drug-stabilised DNA–Topo I cleavable complexes even under continuous TS inhibition. Clonogenic analyses confirmed that these mechanistically distinct drugs at clinically achievable concentrations worked in a highly synergistic manner, with a maximum effect abolishing the viability of virtually all cancer cells (>99.9%). The pretreatment with ZD1694 increased the amount of DNA-bound Topo I by up to 4-fold and the DNA-damaging capability of BNP1100 by up to 15-fold. The possibility of at least four DNA-damaging pathways is proposed which might have resulted from the individual actions of TS and Topo I Inhibitors as well as their concerted actions. Taken together, the present findings provided a logically permissible explanation as to why TS and Topo I Inhibitors in concerted interactions induced a highly lethal effect which was more than a simple additive effect. Since these drugs are effective specifically on actively proliferating cancer cells, but not on non-cycling G 0 /G 1 cells, this mechanism-based protocol may warrant consideration for clinical verification.
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cyclin e cdk2 activation is associated with cell cycle arrest and inhibition of dna replication induced by the Thymidylate Synthase Inhibitor tomudex
Experimental Cell Research, 1999Co-Authors: Mingbiao Yin, Harry K Slocum, Angeles Panadero, Cheryl Frank, Bin Guo, Carol Wrzosek, Youcef M RustumAbstract:Tomudex (ZD1694) is a specific antifolate-based Thymidylate Synthase Inhibitor active in a variety of solid tumor malignancies. Studies were carried out in vitro to evaluate downstream molecular alterations induced as a consequence of the potent and sustained inhibition of Thymidylate Synthase by Tomudex. Twenty-four hours following the initial 2-h treatment with Tomudex, human A253 head and neck squamous carcinoma cells, not expressing p53 and p21(WAF1), were accumulated with DNA content characteristic of early S phase of the cell cycle with a concomitant reduction of cells in G1 and G2/M phases. The changes in cyclin and cdk protein expression and their kinase activities were examined in control and drug-treated A253 cells. 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. Although cyclin A protein expression was markedly increased, cyclin A kinase activity was only slightly increased. Cyclin D1, cyclin B, cdk4, and cdc2 protein expression and kinase activities remain constant. Lack of activation of cyclin A- and B-cdc2 was associated with a reduced proportion of cells in G2/M phases. Increased cyclin E-cdk2 protein expression was accompanied by the inhibition of DNA synthesis, with a decrease in E2F-1 expression. These results propose that cyclin E-cdk2 kinase can negatively regulate DNA replication. The studies with dThyd rescue from cyclin E-cdk2 protein overexpression and growth inhibition by Tomudex indicate that increased cyclin E-cdk2 protein expression is associated with effective inhibition of Thymidylate Synthase and resultant dNTP pool imbalance. Provision of dThyd more than 24 h after exposure to Tomudex allowed cells to replicate DNA for a single cycle back to G1, but did not prevent the profound growth-Inhibitory effect manifested in the following 5 days. Tomudex treatment resulted in a time-dependent induction of the megabase DNA fragments, followed by secondary 50- to 300-kb DNA fragmentation. The 50- to 300-kb DNA fragmentation may be derived from the inhibition of DNA synthesis associated with cyclin E-cdk2 activation. These results suggest that the megabase DNA fragmentation is induced as a consequence of inhibition of Thymidylate Synthase by Tomudex and kilobase DNA fragmentation may correlate with the reduction of p27(kip1) expression and the increase in cyclin E and cdk2 kinase activities. Activation of cyclin E and cdk2 kinases allows cells to transit from G1 to S phase accompanied by the inhibition of DNA synthesis. The changes in cell cycle regulatory proteins associated with growth inhibition and DNA damage by Tomudex are not p53 dependent.
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p53 and waf1 are induced and rb protein is hypophosphorylated during cell growth inhibition by the Thymidylate Synthase Inhibitor zd1694 tomudex
Molecular Pharmacology, 1997Co-Authors: Mingbiao Yin, Wieland Voigt, Angeles Panadero, Udo Vanhoefer, Cheryl Frank, Sanja Pajovic, Jane Clifford Azizkhan, Youcef M RustumAbstract:In a previous study, we found that treatment of HCT-8 cells with ZD1694, a specific antifolate-based Thymidylate Synthase Inhibitor, resulted in DNA fragmentation. 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. WAF1 mRNA showed a time-dependent increase, whereas p53 mRNA was not found to be significantly overexpressed. The initial increase in WAF1 mRNA was detected at 4 hr, but increased WAF1 protein expression was detected 8–24 hr after a 2-hr exposure. The amount of total and hypophosphorylated pRb seems to be rising greatly after ZD1694 exposure. The effects of ZD1694 on the expression of E2F1 and formation of the E2F1-Rb complex were investigated after a 2-hr drug exposure (IC90). The results showed a time-dependent decrease in E2F1 mRNA and protein expression; an increase in the abundance of the E2F-Rb complex could be demonstrated beginning 4 hr after drug exposure by a gel shift assay. Kinetic analysis showed increased availability of hypophosphorylated pRb for inhibition of E2F, which could indirectly result from WAF1-induced inhibition cyclin-dependent kinase activity. Whereas Thymidylate Synthase inhibition by ZD1694 was rapid in onset and maintained for at least 24 hr after drug treatment, drug-induced cellular growth inhibition was significant 24 hr after drug exposure. 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. Therefore, the observed effect on downstream events after effective inhibition of Thymidylate Synthase may offer the critical determinants of response to ZD1694.
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cellular heterogeneity in dna damage and growth inhibition induced by ici d1694 Thymidylate Synthase Inhibitor using single cell assays
Biochemical Pharmacology, 1994Co-Authors: Christoph Schober, John F Gibbs, Mingbiao Yin, Harry K Slocum, Youcef M RustumAbstract:Abstract Heterogeneity in the response of the HCT-8 (human ileocecal adenocarcinoma) tumor cell line to a new Thymidylate Synthase Inhibitor, ICI D1694, was investigated in terms of induction of DNA single-strand breaks and cytotoxicity, applying the single cell alkaline gel (SCG) electrophoresis assay and the individual colony formation assay (iCFA), respectively. ICI D1694 induced maximal total DNA single-strand breaks 24 hr after a 2-hr drug exposure with incomplete repair by 72 hr. The level of DNA damage was concentration dependent and paralleled cellular growth inhibition in vitro. The proportion of cells with DNA damage and the extent of DNA single-strand breaks increased with drug concentration. At 1 μM ICI D1694 ( ic 95), a significant level of DNA damage was detected in 58% of the cells; however, 25% of the cells had little or no damage. Using the iCFA system, it was observed that with 1 μM ICI D1694, only 2.6% of the seeded cells maintained a colony growth rate similar to that of the control colonies, and 22% of the cells were growing significantly more slowly. In conclusion, the SCG assay and the iCFA identified subpopulations of cells that were unaffected by ICI D1694. Although these cells represented only a small proportion of the total cell population, this phenomenon of heterogeneity in response to ICI D1694 might limit its therapeutic efficacy.
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Time Dependence of DNA Lesions and Growth Inhibition by ICI D1694, a New Quinazoline Antifolate Thymidylate Synthase Inhibitor
Cancer research, 1992Co-Authors: Mingbiao Yin, Manoel A. Guimaraes, Zheng-gang Zhang, Mark A. Arredondo, Youcef M RustumAbstract:Abstract DNA single-strand breaks and associated growth inhibition induced by the Thymidylate Synthase Inhibitor N -(5-[ N -(3,4-dihydro-2-methyl-4-oxoquinazoline-6-ylmethyl)- N -methylamino]-2-thenoyl)-l-glutamic acid (ICI D1694) were quantitated using the human ileocecal adenocarcinoma cell line, HCT-8. The effects of different concentrations and schedules of [6R,S]-5-formyltetrahydrofolate ([6RS]LV) and 2′-deoxythymidine (dThd) on drug growth inhibition and DNA damage were also evaluated. The drug concentrations for 50% inhibition of cell growth in culture following 2-h and 72-h exposures were 0.073 and 0.003 µm, respectively. After a 2-h drug exposure, the occurrence of DNA single-strand breaks (SSBs) was time dependent. It was detectable at 8 h and reached a maximum at about 24 h, 34 ± 3 (SD) and 305 ± 34 rad equivalents with 0.1 µm (50% inhibition concentration) and 1.0 µm (90% inhibition concentration) ICI D1694, respectively. A significant level of DNA SSBs (101 ± 13 rad equivalents) was still detectable at 72 h after the 2-h treatment with 1 µm ICI D1694. No significant level of DNA SSBs was detected when cells were exposed simultaneously to ICI D1694 and 20 µm [6RS]LV. Complete rescue of drug-induced DNA SSBs could be achieved when cells were exposed to 10 µm dThd starting no later than 4 h after drug treatment. The growth inhibition of ICI D1694 was abrogated by [6RS]LV in a concentration-dependent manner. Complete protection was achieved when cells were exposed simultaneously to 1 µm ICI D1694 and 5 µm [6RS]LV or to 3 µm dThd immediately after drug treatment. The results demonstrate that: ( a ) the growth inhibition of ICI D1694 is a function of time and schedule; ( b ) the growth inhibition is accompanied by extensive DNA single-strand breaks and slow repair; ( c ) at 1 µm ICI D1694, 3 µm dThd and 5 µm [6RS]LV can completely rescue cells from drug effects when dThd is added up to 4 h following drug treatment or when [6RS]LV is given in combination with the drug; ( d ) interference of [6RS]LV with ICI D1694 action may be occurring at the level of drug uptake and at intracellular targets, while dThd interferes with the drug action at intracellular targets.
F T Boyle - One of the best experts on this subject based on the ideXlab platform.
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent Thymidylate Synthase Inhibitor ZD9331 in mice
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:ZD9331 is a novel, potent Thymidylate Synthase (TS) Inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS Inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.
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zd1694 tomudex a new Thymidylate Synthase Inhibitor with activity in colorectal cancer
European Journal of Cancer, 1995Co-Authors: A L Jackman, K R Harrap, W Gibson, T C Stephens, D C Farrugia, R Kimbell, M Azab, F T BoyleAbstract:Abstract ZD1694 (Tomudex) is a new antifolate which is a specific Inhibitor of Thymidylate Synthase (TS). Evidence suggests that ZD1694 has a spectrum of activity that only partially overlaps with 5-fluorouracil (modulated with leucovorin) against colon tumours in vitro . Potent cytotoxic activity is dependent upon active uptake into cells via the reduced folate/methotrexate cell membrane carrier (RFC) and subsequent metabolism to polyglutamated forms (tri, tetra and pentaglutamates). These polyglutamates are approximately 60-fold more active as TS Inhibitors and are not effluxed readily from cells. Extensive polyglutamation also occurs in various mouse tissues (e.g. small intestinal epithelium, liver and kidney), resulting in high tissue/plasma drug ratios which persist for a prolonged period. ZD1694 has antitumour activity in mice, although the high plasma thymidine in this species complicates: (1) the interpretation of therapeutic index; (2) rumour types in which activity is likely to be observed; and (3) translation of doses and schedules for clinical evaluation. ZD1694 entered clinical study and has completed Phase I and II evaluation, with activity observed in several tumour types. Appreciable activity in the Phase II colorectal study (29% objective response rate on interim analysis) led to the current Phase III study, randomised against 5-fluorouracil/leucovorin.
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mechanisms of acquired resistance to the quinazoline Thymidylate Synthase Inhibitor zd1694 tomudex in one mouse and three human cell lines
British Journal of Cancer, 1995Co-Authors: A L Jackman, G W Aherne, W Gibson, Lloyd R Kelland, R Kimbell, M Brown, Anthea Hardcastle, F T BoyleAbstract:Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in Thymidylate Synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS Inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS Inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation.
G W Aherne - One of the best experts on this subject based on the ideXlab platform.
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent Thymidylate Synthase Inhibitor ZD9331 in mice
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:ZD9331 is a novel, potent Thymidylate Synthase (TS) Inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS Inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.
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comparison of plasma and tissue levels of zd1694 tomudex a highly polyglutamatable quinazoline Thymidylate Synthase Inhibitor in preclinical models
British Journal of Cancer, 1998Co-Authors: G W Aherne, Stephen Clarke, E Ward, N Lawrence, D Dobinson, H Musgrove, F Sutcliffe, T Stephens, A L JackmanAbstract:ZD1694 (Tomudex, raltitrexed) is a specific quinazoline antifolate Thymidylate Synthase Inhibitor that relies on polyglutamation for high potency. Antibodies to ZD1694 have been used to establish a sensitive radioimmunoassay as an alternative to high-performance liquid chromatography (HPLC). The radioimmunoassay is reproducible, accurate and provides a means of determining low levels of ZD1694 in plasma ( 100) were found in dogs treated with a clinically relevant dose of ZD1694. These were maintained for 4 weeks in liver and kidney tissue (> 100). Total gastrointestinal concentrations of ZD1694 were approximately 10 times higher than plasma 3 days after administration, but levels were near to the limit of detection at 4 weeks. These results are consistent with extensive polyglutamation of ZD1694 within tissues in both mice and dog and provide further support for the infrequent schedule that has been used clinically. Although it has not been possible to measure individual polyglutamated forms of ZD1694, the radioimmunoassay provides a convenient means of assessing total drug levels in tissues and is currently the only method suitable for measuring the extent of drug retention in normal tissue and tumour biopsies obtained from patients treated with ZD1694.
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mechanisms of acquired resistance to the quinazoline Thymidylate Synthase Inhibitor zd1694 tomudex in one mouse and three human cell lines
British Journal of Cancer, 1995Co-Authors: A L Jackman, G W Aherne, W Gibson, Lloyd R Kelland, R Kimbell, M Brown, Anthea Hardcastle, F T BoyleAbstract:Four cell lines, the mouse L1210 leukaemia, the human W1L2 lymphoblastoid and two human ovarian (CH1 and 41M) cell lines, were made resistant to ZD1694 (Tomudex) by continual exposure to incremental doses of the drug. A 500-fold increase in Thymidylate Synthase (TS) activity is the primary mechanism of resistance to ZD1694 in the W1L2:RD1694 cell line, which is consequently highly cross-resistant to other folate-based TS Inhibitors, including BW1843U89, LY231514 and AG337, but sensitive to antifolates with other enzyme targets. The CH1:RD1694 cell line is 14-fold resistant to ZD1694, largely accounted for by the 4.2-fold increase in TS activity. Cross-resistance was observed to other TS Inhibitors, including 5-fluorodeoxyuridine (FdUrd). 41M:RD1694 cells, when exposed to 0.1 microM [3H]ZD1694, accumulated approximately 20-fold less 3H-labelled material over 24 h than the parental line. Data are consistent with this being the result of impaired transport of the drug via the reduced folate/methotrexate carrier. Resistance was therefore observed to methotrexate but not to CB3717, a compound known to use this transport mechanism poorly. The mouse L1210:RD1694 cell line does not accumulate ZD1694 or Methotrexate (MTX) polyglutamates. Folylpolyglutamate synthetase substrate activity (using ZD1694 as the substrate) was decreased to approximately 13% of that observed in the parental line. Cross-resistance was found to those compounds known to be active through polyglutamation.
Michael I Walton - One of the best experts on this subject based on the ideXlab platform.
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a rationale for the clinical development of the Thymidylate Synthase Inhibitor zd9331 in ovarian and other solid tumours
Biochimica et Biophysica Acta, 2002Co-Authors: A L Jackman, Davinder S Theti, R Kimbell, L Brunton, Camille Melin, Wynne G Aherne, Michael I WaltonAbstract:Abstract ZD9331 is an antifolate drug that potently and specifically inhibits Thymidylate Synthase (TS). In contrast with TS Inhibitors such as raltitrexed, it cannot be polyglutamated, leading to antitumour activity independent of folylpolyglutamyl synthetase (FPGS) activity. The growth inhibition IC 50 values for ZD9331 and raltitrexed were determined for a panel of 18 human tumour cell lines, that included six colon and six ovarian. The colon lines largely displayed overlapping sensitivities to both drugs with only one of the six lines being drug resistant. In contrast, the ovarian cell lines displayed non-overlapping sensitivities with four being highly resistant to raltitrexed and only one was cross-resistant to ZD9331. Studies were undertaken to explain these results. The colon and ovarian cell lines were characterised for TS activity, and TS and FPGS mRNA expression. TS activity correlated with sensitivity to ZD9331 ( r =0.50; p =0.097) and raltitrexed ( r =0.74; p =0.0063). Provided the data from the highly drug-resistant cell lines (BE and 41 M) were omitted, TS mRNA expression levels also correlated with ZD9331 ( r =0.77; p =0.013) and raltitrexed IC 50 ( r =0.84; p =0.0031). FPGS mRNA expression correlated with higher sensitivity to raltitrexed relative to ZD9331 (higher ZD9331/raltitrexed IC 50 ratios) ( r =0.62; p =0.048). Similarly, cell lines with IC 50 ratios>median expressed a 1.8-fold higher median level of FPGS mRNA ( p =0.0087) compared with those with ratios≤median. The four ovarian and one colon cell line that were relatively more sensitive to ZD9331 expressed FPGS mRNA≤median ( p =0.061). Thus, ZD9331 overcomes resistance to raltitrexed in ovarian tumour cell lines expressing low levels of FPGS. These data, and others demonstrating a lack of cross-resistance between cisplatin and ZD9331, support the clinical evaluation of ZD9331 in platinum-refractory ovarian cancer.
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent Thymidylate Synthase Inhibitor ZD9331 in mice
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the renal effects of the water soluble non folylpolyglutamate synthetase dependent Thymidylate Synthase Inhibitor zd9331 in mice
British Journal of Cancer, 1998Co-Authors: Michael I Walton, F T Boyle, F Mitchell, G W Aherne, C J Medlow, A L JackmanAbstract:ZD9331 is a novel, potent Thymidylate Synthase (TS) Inhibitor which does not require polyglutamation by folylpolyglutamate synthetase (FPGS) for its activity. In contrast to Tomudex (ZD1694), ZD9331 may therefore be active against tumours with low FPGS activity. ZD9331 shows anti-tumour activity by both 24-h infusion and bolus administration in the murine thymidine kinase-deficient (TK -/-) lymphoma L5178Y. In view of the history of renal toxicity with some earlier TS Inhibitors and the possible therapeutic use of bolus ZD9331, we have examined the effects of bolus ZD9331 dose and route of administration on plasma and kidney pharmacokinetics and renal function in mice. Renal function was assessed by measuring [14C]inulin clearance, and drug concentrations were assayed by reverse-phase high-performance liquid chromatography (HPLC). Renal function was unaffected by ZD9331 up to 150 mg kg(-1) either i.v. or i.p. However, at 200 mg kg(-1), glomerular filtration rate was significantly inhibited following i.v. but not i.p. administration. Pharmacokinetic studies showed that these effects were consistent with the markedly higher plasma drug concentrations occurring during early times following i.v. dosing, although the plasma drug profiles were otherwise similar for both routes. Kidney drug concentrations were slightly elevated in i.v.- versus i.p.-treated animals at the low dose (50 mg kg(-1)), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg(-1)), peak kidney drug concentrations were 20-fold higher following i.v. administration than after i.p., with marked kidney retention, resulting in a 50-fold greater kidney drug exposure for the i.v. versus the i.p. route. These data show that ZD9331 is non-nephrotoxic at active anti-tumour doses (50 mg kg(-1) i.p.) in mice, and only at very high bolus i.v. doses is there impaired renal function as a result of very high peak plasma concentrations. These adverse effects can be readily overcome by i.p. administration, indicating the likely need for short infusions in clinical settings.