Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1991 Nov;64(5):833–838. doi: 10.1038/bjc.1991.409

The renal effects of N10-propargyl-5,8-dideazafolic acid (CB3717) and a non-nephrotoxic analogue ICI D1694, in mice.

D I Jodrell 1, D R Newell 1, S E Morgan 1, S Clinton 1, J P Bensted 1, L R Hughes 1, A H Calvert 1
PMCID: PMC1977485  PMID: 1931603

Abstract

N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)- N-methylamino]-2-thenoyl)-L-glutamic acid (ICI D1694) is an analogue of the thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid (CB3717). CB3717 was found to be active in early clinical studies, but its use was limited by nephrotoxicity. ICI D1694 is a more potent antitumour agent than CB3717 and is also more water soluble. Previous studies have shown ICI D1694 to be non-toxic to the kidney following a single administration but its renal effects after chronic administration are unknown. To assess these effects, and further define the time course and dose relationship of CB3717-induced renal damage, an assay of glomerular filtration rate (GFR) has been developed which can be used in mice and hence in the screening of novel compounds. The 14C-inulin clearance assay developed was used to show a linear relationship between CB3717 dosage and renal damage (r = - 0.989) following a single bolus dose (50-200 mg kg-1), in mice. CB3717-induced renal damage is persistent (greater than 6 weeks) and renal scarring was noted. ICI D1694 has been shown to be non-nephrotoxic following weekly administration of 250 mg kg-1 for 6 weeks. Measurement of GFR has been shown to be a more sensitive indicator of impaired renal function than plasma urea and creatine concentration, and the measurement of plasma creatinine concentration in particular, appears to be without value in the screening of potential nephrotoxins in certain mouse strains.

Full text

PDF
833

Images in this article

836Plate 1
on p.836
836Plate 2
on p.836
836Plate 3
on p.836
836Plate 4
on p.836
836Plate 5
on p.836

Selected References

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

  1. Bassendine M. F., Curtin N. J., Loose H., Harris A. L., James O. F. Induction of remission in hepatocellular carcinoma with a new thymidylate synthase inhibitor, CB3717. A phase II study. J Hepatol. 1987 Jun;4(3):349–356. doi: 10.1016/s0168-8278(87)80545-7. [DOI] [PubMed] [Google Scholar]
  2. Bryan C. W., Jarchow R. C., Maher J. F. Measurement of glomerular filtration rate in small animals without urine collection. J Lab Clin Med. 1972 Dec;80(6):845–856. [PubMed] [Google Scholar]
  3. Calvert A. H., Alison D. L., Harland S. J., Robinson B. A., Jackman A. L., Jones T. R., Newell D. R., Siddik Z. H., Wiltshaw E., McElwain T. J. A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. J Clin Oncol. 1986 Aug;4(8):1245–1252. doi: 10.1200/JCO.1986.4.8.1245. [DOI] [PubMed] [Google Scholar]
  4. Cantwell B. M., Macaulay V., Harris A. L., Kaye S. B., Smith I. E., Milsted R. A., Calvert A. H. Phase II study of the antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717) in advanced breast cancer. Eur J Cancer Clin Oncol. 1988 Apr;24(4):733–736. doi: 10.1016/0277-5379(88)90307-0. [DOI] [PubMed] [Google Scholar]
  5. Daugaard G., Rossing N., Rørth M. Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemother Pharmacol. 1988;21(2):163–167. doi: 10.1007/BF00257365. [DOI] [PubMed] [Google Scholar]
  6. Harrap K. R., Jackman A. L., Newell D. R., Taylor G. A., Hughes L. R., Calvert A. H. Thymidylate synthase: a target for anticancer drug design. Adv Enzyme Regul. 1989;29:161–179. doi: 10.1016/0065-2571(89)90099-x. [DOI] [PubMed] [Google Scholar]
  7. Newell D. R., Alison D. L., Calvert A. H., Harrap K. R., Jarman M., Jones T. R., Manteuffel-Cymborowska M., O'Connor P. Pharmacokinetics of the thymidylate synthase inhibitor N10-propargyl-5,8-dideazafolic acid (CB3717) in the mouse. Cancer Treat Rep. 1986 Aug;70(8):971–979. [PubMed] [Google Scholar]
  8. Sessa C., Zucchetti M., Ginier M., Willems Y., D'Incalci M., Cavalli F. Phase I study of the antifolate N10-propargyl-5,8-dideazafolic acid, CB 3717. Eur J Cancer Clin Oncol. 1988 Apr;24(4):769–775. doi: 10.1016/0277-5379(88)90313-6. [DOI] [PubMed] [Google Scholar]
  9. Vest S., Bork E., Hansen H. H. A phase I evaluation of N10-propargyl-5,8-dideazafolic acid. Eur J Cancer Clin Oncol. 1988 Feb;24(2):201–204. doi: 10.1016/0277-5379(88)90253-2. [DOI] [PubMed] [Google Scholar]
  10. Von Hoff D. D., Schilsky R., Reichert C. M., Reddick R. L., Rozencweig M., Young R. C., Muggia F. M. Toxic effects of cis-dichlorodiammineplatinum(II) in man. Cancer Treat Rep. 1979 Sep-Oct;63(9-10):1527–1531. [PubMed] [Google Scholar]

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

RESOURCES