ZD1694 (Tomudex): A new thymidylate synthase inhibitor with activity in colorectal cancer

Jackman, Ann L.; Farrugia, David; Gibson, William A.; Kimbell, Rosemary; Harrap, K. R.; Stephens, T C; Azab, M; Boyle, F.T

doi:10.1016/0959-8049(95)00166-g

Cited by 94 publications

(55 citation statements)

References 12 publications

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“…To confirm that thymidine was able to relieve inhibition of TS in vivo, the highly specific quinazoline TS inhibitor Tomudex (10 mg͞kg; reviewed in ref. 17) was administered alone or with thymidine. Fig.…”

Section: -Fu-induced Apoptosis In Crypt Epitheliamentioning

confidence: 99%

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Pritchard

Watson

Potten

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

175

133

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The epithelia from the crypts of the intestine are exquisitely sensitive to metabolic perturbation and undergo cell death with the classical morphology of apoptosis. Administration of 40 mg͞kg 5-f luorouracil (5-FU) to BDF-1 p53؉͞؉ mice resulted in an increase in p53 protein at cell positions in the crypts that were also those subjected to an apoptotic cell death. In p53؊͞؊ mice apoptosis was almost completely absent, even after 24 hr. 5-FU is a pyrimidine antimetabolite cytotoxin with multiple mechanisms of action, including inhibition of thymidylate synthase (TS), which gives rise to DNA damage, and incorporation into RNA. The inhibition of TS can be increased by coadministration of folinic acid and can be abrogated by administration of thymidine. The incorporation of 5-FU into RNA is inhibited by administration of uridine. p53-Dependent cell death induced by 5-FU was only inhibited by administration of uridine. Uridine had no effect on the apoptosis initiated by 1 Gy of ␥-radiation. Although thymidine abrogated apoptosis induced by the pure TS inhibitor Tomudex, it had no effect on 5-FU-induced apoptosis, and coadministration of folinic acid did not increase apoptosis. The data show that 5-FU-induced cell death of intestinal epithelial cells is p53-dependent and suggests that changes in RNA metabolism initiate events culminating in the expression of p53.

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Section: -Fu-induced Apoptosis In Crypt Epitheliamentioning

confidence: 99%

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Pritchard

Watson

Potten

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

175

133

View full text Add to dashboard Cite

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“…The prolonged inhibition of TS in intact cells (Jackman et al, 1995b;Aheme et al, 1996a), even after removal of drug from the medium, is consistent with the formation and retention of active intracellular polyglutamated species. High circulating levels of thymidine in mouse models compared with those in man complicate the anti-tumour evaluation of TS inhibitors (Jackman et al, 1984(Jackman et al, , 1995a, but ZD1694 was curative in DBA2 mice bearing the intramuscular L5178Y TK-/-mouse lymphoma by a single i.p. injection (10 mg kg-') (Jackman et al, 1991b).…”

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confidence: 99%

“…In recent years this enzyme has received much attention as a chemotherapeutic target (Nord and Martin, 1993;Jackman and Calvert, 1995), and several compounds are at various stages of drug development. One of these, ZD1694 (Tomudex, raltitrexed), a quinazoline antifolate (Jackman et al, 1991a(Jackman et al, , 1995a, has progressed to broad phase II Smith et al, 1996) and phase III clinical studies in advanced colorectal cancer . Tomudex is now available for the treatment of advanced colorectal cancer in several countries.…”

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confidence: 99%

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Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

Aherne

Ward²,

Lawrence³

et al. 1998

Br J Cancer

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Summary ZD1 694 (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 (< 1 nM). By virtue of the high cross-reactivity of the antibodies with polyglutamated forms of ZD1 694, it is also possible to measure the total concentration of drug in tissues. Results obtained in L1210 mouse leukaemia cells and in mouse tissues were similar to those previously determined using radiolabelled drug. Pharmacokinetic studies in mice have confirmed that the compound is rapidly eliminated from the plasma and that there is a prolonged terminal elimination phase. ZD1694 was measured in plasma (0.56 ng ml-1; 1.2 pmol ml-') up to 7 days after a single i.p. dose of 100 mg kg-' ZD1 694. Liver, kidney and gut epithelium had a substantially higher level of ZD1 694 immunoreactivity than plasma. For example, 24 h after a single i.p. dose at 1, 10 and 100 mg kg-', total drug levels in the liver were 480, 325 and 152 times higher than plasma levels respectively. In kidney and gut epithelium, total drug levels at these doses were approximately 55 and 34 times those of plasma. The high tissue to plasma ratios were maintained for at least 7 days after administration. Similarly, high tissue to plasma ratios (> 100) were found in dogs treated with a clinically relevant dose of ZD1 694. 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 ZD1 694 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 ZD1 694, 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 ZD1 694.

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“…Subsequently, the quinazoline TS inhibitor Tomudex (ZD1694) was developed as a non-nephrotoxic compound with clinical anti-tumour activity (Clarke et al, 1993;Jackman et al, 1996). Tomudex can be administered by 15-min infusion and shows anti-tumour activity in clinical studies (Jackman et al, 1995a. ZD1694 is rapidly transported into cells via the reduced folate carrier (RFC) and requires polyglutamation by folylpolyglutamate synthetase (FPGS) to form more potent penta-polyglutamated TS inhibitors (Jackman et al, 1991;Gibson et al, 1993).…”

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confidence: 99%

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

Walton

Mitchell²,

Aherne³

et al. 1998

Br J Cancer

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Summary 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-', 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 iv.-versus i.p.-treated animals at the low dose (50 mg kg-'), with a correspondingly larger area under the curve. However, at the highest dose (200 mg kg-'), 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-' 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

Cited by 94 publications

References 12 publications

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Inhibition by uridine but not thymidine of p53-dependent intestinal apoptosis initiated by 5-fluorouracil: Evidence for the involvement of RNA perturbation

Comparison of plasma and tissue levels of ZD1694 (Tomudex), a highly polyglutamatable quinazoline thymidylate synthase inhibitor, in preclinical models

The renal effects of the water-soluble, non-folylpolyglutamate synthetase-dependent thymidylate synthase inhibitor ZD9331 in mice

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