Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1998;77(Suppl 2):29–37. doi: 10.1038/bjc.1998.423

New developments in cancer treatment with the novel thymidylate synthase inhibitor raltitrexed ('Tomudex').

G Blackledge 1
PMCID: PMC2149719  PMID: 9579853

Abstract

Following the demonstration of efficacy, tolerability and quality-of-life benefits of raltitrexed ('Tomudex'), principally in advanced colorectal but also in other cancers, an extensive evaluation of combination therapy with other agents in patients with colorectal and other tumour types is being undertaken. This work has been prompted by preclinical observations of enhanced activity of raltitrexed when coadministered with other cytotoxic agents or radiotherapy and by preliminary results showing the activity of raltitrexed in patients with cancers other than colorectal. Raltitrexed is currently being investigated as monotherapy in phase I and II cancer studies, including head and neck cancer, hormone-resistant prostate cancer, paediatric and adult leukaemias and solid tumours, and soft tissue sarcoma. In addition, phase I clinical trials are evaluating the drug in combination with taxanes (paclitaxel) in solid tumours, anthracyclines (doxorubicin) in gastric carcinoma, topoisomerase I inhibitors (CPT-11) and 5-fluorouracil (both infusion and bolus regimens) in advanced colorectal cancer, platinum compounds (oxaliplatin and cisplatin) in a variety of tumours and radiotherapy in rectal cancer. Preliminary reports indicate good tolerability and acceptability of the combinations being investigated, with no dose-limiting toxicity being reported to date, and some early indications of efficacy.

Full text

PDF
29

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allen-Mersh T. G., Earlam S., Fordy C., Abrams K., Houghton J. Quality of life and survival with continuous hepatic-artery floxuridine infusion for colorectal liver metastases. Lancet. 1994 Nov 5;344(8932):1255–1260. doi: 10.1016/s0140-6736(94)90750-1. [DOI] [PubMed] [Google Scholar]
  2. Armand J. P., Ducreux M., Mahjoubi M., Abigerges D., Bugat R., Chabot G., Herait P., de Forni M., Rougier P. CPT-11 (irinotecan) in the treatment of colorectal cancer. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1283–1287. doi: 10.1016/0959-8049(95)00212-2. [DOI] [PubMed] [Google Scholar]
  3. Binder C., Marx D., Binder L., Schauer A., Hiddemann W. Expression of Bax in relation to Bcl-2 and other predictive parameters in breast cancer. Ann Oncol. 1996 Feb;7(2):129–133. doi: 10.1093/oxfordjournals.annonc.a010538. [DOI] [PubMed] [Google Scholar]
  4. Cunningham D., Zalcberg J. R., Rath U., Oliver I., van Cutsem E., Svensson C., Seitz J. F., Harper P., Kerr D., Perez-Manga G. Final results of a randomised trial comparing 'Tomudex' (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. "Tomudex" Colorectal Cancer Study Group. Ann Oncol. 1996 Nov;7(9):961–965. doi: 10.1093/oxfordjournals.annonc.a010800. [DOI] [PubMed] [Google Scholar]
  5. Cunningham D., Zalcberg J., Smith I., Gore M., Pazdur R., Burris H., 3rd, Meropol N. J., Kennealey G., Seymour L. 'Tomudex' (ZD1694): a novel thymidylate synthase inhibitor with clinical antitumour activity in a range of solid tumours. 'Tomudex' International Study Group. Ann Oncol. 1996 Feb;7(2):179–182. doi: 10.1093/oxfordjournals.annonc.a010546. [DOI] [PubMed] [Google Scholar]
  6. Engin A. Differences in blood glutathione levels of patients with advanced or localized carcinoma. Tumori. 1995 Mar-Apr;81(2):132–134. doi: 10.1177/030089169508100212. [DOI] [PubMed] [Google Scholar]
  7. Horne G. M., Anderson J. J., Tiniakos D. G., McIntosh G. G., Thomas M. D., Angus B., Henry J. A., Lennard T. W., Horne C. H. p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry. Br J Cancer. 1996 Jan;73(1):29–35. doi: 10.1038/bjc.1996.6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Horwitz S. B. Taxol (paclitaxel): mechanisms of action. Ann Oncol. 1994;5 (Suppl 6):S3–S6. [PubMed] [Google Scholar]
  9. Jackman A. L., Farrugia D. C., Gibson W., Kimbell R., Harrap K. R., Stephens T. C., Azab M., Boyle F. T. ZD1694 (Tomudex): a new thymidylate synthase inhibitor with activity in colorectal cancer. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1277–1282. doi: 10.1016/0959-8049(95)00166-g. [DOI] [PubMed] [Google Scholar]
  10. Jackman A. L., Taylor G. A., Gibson W., Kimbell R., Brown M., Calvert A. H., Judson I. R., Hughes L. R. ICI D1694, a quinazoline antifolate thymidylate synthase inhibitor that is a potent inhibitor of L1210 tumor cell growth in vitro and in vivo: a new agent for clinical study. Cancer Res. 1991 Oct 15;51(20):5579–5586. [PubMed] [Google Scholar]
  11. Kelland L. R., Kimbell R., Hardcastle A., Aherne G. W., Jackman A. L. Relationships between resistance to cisplatin and antifolates in sensitive and resistant tumour cell lines. Eur J Cancer. 1995 Jun;31A(6):981–986. doi: 10.1016/0959-8049(95)00198-0. [DOI] [PubMed] [Google Scholar]
  12. Lévi F. A., Zidani R., Vannetzel J. M., Perpoint B., Focan C., Faggiuolo R., Chollet P., Garufi C., Itzhaki M., Dogliotti L. Chronomodulated versus fixed-infusion-rate delivery of ambulatory chemotherapy with oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients with colorectal cancer metastases: a randomized multi-institutional trial. J Natl Cancer Inst. 1994 Nov 2;86(21):1608–1617. doi: 10.1093/jnci/86.21.1608. [DOI] [PubMed] [Google Scholar]
  13. Lévi F., Giacchetti S., Adam R., Zidani R., Metzger G., Misset J. L. Chronomodulation of chemotherapy against metastatic colorectal cancer. International Organization for Cancer Chronotherapy. Eur J Cancer. 1995 Jul-Aug;31A(7-8):1264–1270. doi: 10.1016/0959-8049(95)00242-b. [DOI] [PubMed] [Google Scholar]
  14. Lévi F., Misset J. L., Brienza S., Adam R., Metzger G., Itzakhi M., Caussanel J. P., Kunstlinger F., Lecouturier S., Descorps-Declère A. A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin using an ambulatory multichannel programmable pump. High antitumor effectiveness against metastatic colorectal cancer. Cancer. 1992 Feb 15;69(4):893–900. doi: 10.1002/1097-0142(19920215)69:4<893::aid-cncr2820690410>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  15. Mayer R. J., O'Connell M. J., Tepper J. E., Wolmark N. Status of adjuvant therapy for colorectal cancer. J Natl Cancer Inst. 1989 Sep 20;81(18):1359–1364. doi: 10.1093/jnci/81.18.1359. [DOI] [PubMed] [Google Scholar]
  16. McKeage M. J. Comparative adverse effect profiles of platinum drugs. Drug Saf. 1995 Oct;13(4):228–244. doi: 10.2165/00002018-199513040-00003. [DOI] [PubMed] [Google Scholar]
  17. Moertel C. G. Chemotherapy for colorectal cancer. N Engl J Med. 1994 Apr 21;330(16):1136–1142. doi: 10.1056/NEJM199404213301608. [DOI] [PubMed] [Google Scholar]
  18. Rougier P., Bugat R. CPT-11 in the treatment of colorectal cancer: clinical efficacy and safety profile. Semin Oncol. 1996 Feb;23(1 Suppl 3):34–41. [PubMed] [Google Scholar]
  19. Rougier P., Ducreux M., Kerr D., Carr B. I., François E., Adenis A., Seymour L. A phase II study of raltitrexed ('Tomudex') in patients with hepatocellular carcinoma. Ann Oncol. 1997 May;8(5):500–502. doi: 10.1023/a:1008249328792. [DOI] [PubMed] [Google Scholar]
  20. Rowinsky E. K., Cazenave L. A., Donehower R. C. Taxol: a novel investigational antimicrotubule agent. J Natl Cancer Inst. 1990 Aug 1;82(15):1247–1259. doi: 10.1093/jnci/82.15.1247. [DOI] [PubMed] [Google Scholar]
  21. Rowinsky E. K., Donehower R. C. Paclitaxel (taxol) N Engl J Med. 1995 Apr 13;332(15):1004–1014. doi: 10.1056/NEJM199504133321507. [DOI] [PubMed] [Google Scholar]
  22. Rustum Y. M., Harstrick A., Cao S., Vanhoefer U., Yin M. B., Wilke H., Seeber S. Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors. J Clin Oncol. 1997 Jan;15(1):389–400. doi: 10.1200/JCO.1997.15.1.389. [DOI] [PubMed] [Google Scholar]
  23. Scheithauer W., Rosen H., Kornek G. V., Sebesta C., Depisch D. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ. 1993 Mar 20;306(6880):752–755. doi: 10.1136/bmj.306.6880.752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Schiff P. B., Horwitz S. B. Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1561–1565. doi: 10.1073/pnas.77.3.1561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Seidman A. D. The emerging role of paclitaxel in breast cancer therapy. Clin Cancer Res. 1995 Mar;1(3):247–256. [PubMed] [Google Scholar]
  26. Sobrero A. F., Aschele C., Bertino J. R. Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. J Clin Oncol. 1997 Jan;15(1):368–381. doi: 10.1200/JCO.1997.15.1.368. [DOI] [PubMed] [Google Scholar]
  27. Touroutoglou N., Pazdur R. Thymidylate synthase inhibitors. Clin Cancer Res. 1996 Feb;2(2):227–243. [PubMed] [Google Scholar]
  28. Van Roy N., Cheng N. C., Laureys G., Opdenakker G., Versteeg R., Speleman F. Molecular cytogenetic analysis of 1;17 translocations in neuroblastoma. Eur J Cancer. 1995;31A(4):530–535. doi: 10.1016/0959-8049(95)00004-3. [DOI] [PubMed] [Google Scholar]
  29. Verweij J., Schellens J. H. Topoisomerase I inhibition: a new target or new missiles? Ann Oncol. 1995 Feb;6(2):102–104. doi: 10.1093/oxfordjournals.annonc.a059100. [DOI] [PubMed] [Google Scholar]
  30. Zalcberg J. Overview of the tolerability of 'Tomudex' (raltitrexed): collective clinical experience in advanced colorectal cancer. Anticancer Drugs. 1997 Aug;8 (Suppl 2):S17–S22. doi: 10.1097/00001813-199708002-00004. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES