A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq® (nolatrexed dihydrochloride) given by 10-day oral administration

British Journal of Cancer

Volumn 79, Issue 5-6, 1999, Pages 915-920

  Jodrell, D I ^a   Bowman, A ^a   Rye, R ^a   Byrne, B ^a   Boddy, A ^b   Rafi, I ^b   Taylor, G A ^b   Johnston, A ^c   Clendeninn, N J ^c  

^a WESTERN GENERAL HOSPITAL   (United Kingdom)

^b NEWCASTLE UNIVERSITY   (United Kingdom)

^c AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

10 Day administration; Nolatrexed; Oral; Phase I

Indexed keywords

NOLATREXED; THYMIDYLATE SYNTHASE INHIBITOR;

ADULT; AGED; ARTICLE; CLINICAL ARTICLE; CLINICAL TRIAL; COLORECTAL CANCER; FEMALE; HUMAN; LUNG CANCER; MALE; NAUSEA; NEUTROPENIA; ORAL DRUG ADMINISTRATION; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; RASH; STOMATITIS; THROMBOCYTOPENIA; VOMITING;

ADMINISTRATION, ORAL; ADULT; ANTIMETABOLITES, ANTINEOPLASTIC; BIOLOGICAL AVAILABILITY; DEOXYURIDINE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG ADMINISTRATION SCHEDULE; EXANTHEMA; HUMANS; LIVER FUNCTION TESTS; NAUSEA; NEOPLASMS; NEUTROPENIA; QUINAZOLINES; STOMATITIS; THROMBOCYTOPENIA; THYMIDYLATE SYNTHASE; VOMITING;

EID: 0033037357     PISSN: 00070920     EISSN: None     Source Type: Journal    
DOI: 10.1038/sj.bjc.6690146     Document Type: Article

References (18)

1. Appelt K, Bacquet RJ, Bartlett CA, Booth CL, Freer ST, Fuhry MA, Gehring MR, Herrmann SM, Howland EF and Janson CA (1991) Design of enzyme inhibitors using iterative protein crystallographic analysis. J Med Chem 34: 1925-1934
2. Bassendine MF, Curtin NJ, Loose H, Harris AL and James OJW (1987) Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. J Hepatol 4: 349
3. Calvert AH, Alison DL, Harland SJ, Robinson BA, Jackman AL, Jones TR, Newell DR, Siddik ZH, Wiltshaw E and McElwain TJ (1986) A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol 4: 1245-1252
4. Calvert AH, Newell DR, Jackman AL, Gumbrell LA, Sikora E, Grzelakowska-Sztabert B, Bishop JA, Judson IR, Harland SJ and Harrap KR (1987) Recent preclinical and clinical studies with the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB 3717). NCI Monogr: 213-218
5. Cantwell BM, Macaulay V, Harris AL, Kaye SB, Smith IE, Milsted RA and Calvert AH (1988) Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer. Eur J Cancer Clin Oncol 24: 733-736
6. Clendeninn NJ, Collier MA, Johnston AL, Loh KK, Cohn A, Kelly K, Glode LM, Stuart KE and Belani CP (1996) Thymitaq (AG337): a novel thymidylate synthase inhibitor with clinical activity in solid tumours. Proc Am Assoc Cancer Res 37: 171
7. Creaven PJ, Pendyala L, Meopol NJ, Clendeninn NJ, Wu EY, Loewen GM, Proefrock A, Johnston A and Dixon M (1998) Initial clinical trial and pharmacokinetics of Thymitaq (AG337) by 10-day continuous infusion in patients with advanced solid tumors. Cancer Chemother Pharmacol 41: 167-170
8. Jackman AL, Taylor GA, Gibson W, Kimbell R, Brown M, Calvert AH, Judson IR and Hughes LR (1991) ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of LI210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res 51: 5579-5586
9. Jackson RC. Design and development of lipophilic inhibitors of thymidylate synthase. Proc Am Assoc Cancer Res 33: 592-593
10. Jodrell DI, Newell DR, Morgan SE, Clinton S, Bensted JP, Hughes LR and Calvert AH (1991) The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice. Br J Cancer 64: 833-838
11. Pinedo HM and Peters GF (1988) Flurouracil: biochemistry and pharmacology. J Clin Oncol 6: 1653-1664
12. Rafi I, Taylor GA, Calvete JA, Boddy AV, Balmanno K, Bailey N, Lind M, Calvert AH, Webber S, Jackson RC, Johnston A, Clendeninn N and Newell DR (1995) Clinical pharmacokinetic and pharmacodynamic studies with the non-classical antifolate thymidylate synthase inhibitor 2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (AG337) given by 24 hour continuous intravenous infusion. Clin Cancer Res 1: 1275-1284
13. Rafi I, Boddy AV, Taylor GA, Calvete JA, Bailey NB, Lind MJ, Newell DR, Calvert AH, Johnston A and Clendeninn NJ (1996) A phase I clinical study of the novel antifolate AG337 given by 5 day oral administration. Proc Am Assoc Cancer Res 37: 178
14. Rafi I, Boddy AV, Calvete JA, Taylor GA, Newell DR, Bailey N, Lind MJ, Johnston A, Clendeninn N and Calvert AH (1998) Pre-clinical and phase I clinical studies with the non-classical antifolate thymidylate synthase inhibitor Thymitaq (AG337) given by prolonged administration. J Clin Oncol 16: 1131-1141
15. Santi DV, McHenry CS and Sommer H (1974) Mechanism of interaction of thymidylate synthetase with 5-fluorodeoxyuridylate. Biochemistry 13: 471-481
16. US Patent Application filed 31 March 1992
17. Valeriote F and Santelli G (1984) 5-Fluorouracil (FUra). Pharmacol Ther 24: 107-132
18. Webber S, Bartlett CA, Boritzki TJ, Hillard JA, Howland EF, Johnston AL, Kosa M, Margosiak SA, Morse CA and Shetty BV (1996) AG337, a novel lipophilic thymidylate synthase inhibitor: in vitro and in vivo preclinical studies. Cancer Chemother Pharmacol 37: 509-517