Summary
The influence of the treatment schedule of dianhydrogalactitol on its effect on the activity of mucosal enzymes in rat intestine was studied. The effect of a single high dose (10 mg/kg) was compared with that of repeated small doses (4x2.5 mg/kg) given at daily intervals. At 48 h after a single high dose the activities of thymidine kinase, which is a marker of dividing crypt cells, and of alkaline phosphatase, sucrase, maltase, xanthine oxidase, which are markers of mature enterocytes, were strongly depressed. Even 96 h after the treatment low enzyme activities could be observed. Repeated small doses caused milder enzyme inhibition and almost total recovery had occurred by 96 h after administration of the last dose. The results indicate that fractionation of drug administration can reduce the toxic side-effects on the intestinal mucosa and might be partly responsible for the higher therapeutic index of such schedules in experimental tumor models.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- AG:
-
dianhydrogalactitol
- LD50 :
-
dose of drug causing 50% lethality
- TK:
-
thymidine kinase EC 2.7.1.21
- AP:
-
alkaline phosphatase EC 3.1.3.1
- SUC:
-
sucrase EC 3.2.1.26
- MAL:
-
maltase EC 3.2.1.20
- XO:
-
xanthine oxidase EC 1.2.3.2
References
Achord JL (1969) The effect of methotrexate on rabbit intestinal mucosal enzymes and flora. Am J Dig Dis 14:315
Bessey OA, Lowry OH, Brock MI (1965) Determination in serum with p-nitrophenylphosphate. In: Bergmeyer HU (ed) Methods of enzymatic analysis. Verlag Chemie, Weinheim/ Academic Press, New York London, p 783
Chiuten DF, Rozencweig M, von Hoff DD, Muggia FM (1981) Clinical trials with hexitol derivatives in the US. Cancer 47:447
Cohen MI, McNamara H (1970) The effect of colchicine on guinea pig intestinal enzyme activity. Am J Dig Dis 15:247
Dahlquist A (1968) Assay of intestinal disaccharidases. Anal Biochem 22:99
De Both NJ, Plaisier H (1974) The influence of changing cell kinetics on functional differentiation in the small intestine of the rat. J Histochem Cytochem 22:352
Eagan RT, Moertel CG, Hahn RG, Schutt AJ (1976) Phase I study of a five-day intermittent schedule for 1,2:5,6-dianhydrogalactitol (NSC-132313). J Natl Cancer Inst 56:179
Ecknauer R (1976) Morphology and enzyme activity in rat small intestinal epithelium 6 and 12 h after an alkylating agent. Acta Hepatogastroenterol (Stuttg) 23:365
Ecknauer R, Rommel K (1978) Zytostatika und Dünndarm. Klin Wochenschr 56:579
Espana P, Wiernik PH, Walker MD (1978) Phase II study of dianhydrogalactitol in malignant glioma. Cancer Treat Rep 62:1199
Grand RJ, Chong OA, Isselbacher KJ (1971) Intracellular processing of disaccharidases. The effect of actinomycin D. Biochim Biophys Acta 261:341
Haas CD, Stephens RL, Hollister M, Hoogstraten B (1976) Phase I evaluation of dianhydrogalactitol (NSC-132313). Cancer Treat Rep 60:611
Hartwich G (1974) Side-effects of a cytostatic treatment on the gastrointestinal tract. Acta Hepatogastroenterol (Stuttg) 21:89
Hernádi F, Kovács P, Ujj G, Kerpel-Fronius S, Somfai-Relle S (1980) Effect of repeated doses of dianhydrogalactitol on murine bone marrow colony-forming units in culture. In: Nelson JD, Grassi C (eds) Current chemotherapy and infectious diseases, vol 2. American Society for Microbiology, Washington, p 1608
Klemperer C, Haynes J (1968) Thymidine kinase in rat liver during development. Biochem J 108:541
Kralovánszky J, Prajda N, Kerpel-Fronius S, Szentirmay Z (1981) Biological model system for investigating gastrointestinal side-effects caused by cytostatic agents. In: Mózsik Gy, Hänninen O, Jávor T (eds) Gastrointestinal defence mechanisms. Pergamon Press, London/Akadémiai Kiadó, Budapest, p 327
Lowry OH, Rosenbrough NJ, Farr AL, Randall RJ (1951) Protein measurment with the Folin phenol reagent. J Biol Chem 193:265
Marano R, Pastore G, Manghisi O, Schiraldi O (1969) Effect of aminopterin and antibiotics on disaccharidase activity of the rat small bowel. Experientia 25:1284
Németh L, Institóris L, Somfai S, Gál F, Pályi I, Sugár J, Csuka O, Szentirmay Z, Kellner B (1972) Pharmacologic and antitumor effect of 1,2:5,6-dianhydrogalactitol (NSC 132313). Cancer Chemother Rep 56:593
Palme G, Liss E, Wiebel F (1964) Autoradiographische Untersuchungen suchungen über das Verhalten einzelner Interphasenabschnitte des Dünndarmepithels der Maus unter der Einwirkung von Cyclophosphamid. Naturwissenschaften 51:197
Prajda N, Weber G (1975) Malignant transformation-linked imbalance: Decreased xanthine oxidase activity in hepatomas. FEBS Lett 59:245
Prajda N, Kralovánszky J, Kerpel-Fronius S, Gál F (1981) Effect of dianhydrogalactitol on biochemical and morphological characteristics of the rat intestinal mucosa. In: Mózsik Gy, Hänninen O, Jávor T (eds) Gastrointestinal defence mechanisms. Pergamon Press, London/Akadémiai Kiadó, Budapest, p 339
Rommel K, Naupert Ch, Grimmel K (1969) Wirkung von Cyclophosphamid (Endoxan) auf die Disaccharidasenaktivität der Dünndarmschleimhaut der Ratte. Z Gastroenterol 7:474
Somfai-Relle S, Németh L (1982) Cumulation of toxic effects of DBD. In: Eckhardt S (ed) Dibromodulcitol. Medicina Press, Budapest, p 38
Vogel CL, Winton EF, Moore MR, Sohner S (1976) Phase I trial of dianhydrogalactiol administered i.v. in a weekly schedule. Cancer Treat Rep 60:895
Waldeck HH (1972) Die Dünndarmschleimhaut nach hohen Dosen Cyclophosphamid. Morphologische und histochemische Untersuchungen beim Goldhamster. Z Gastroenterol 10:543
Weiser MM (1973) Intestinal epithelial cell surface membrane glycoprotein synthesis. J Biol Chem 248:2536
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Kralovánszky, J., Prajda, N., Kerpel-Fronius, S. et al. Effect of a single high dose and repeated small doses of dianhydrogalactitol (DAG; NSC-132313) on rat intestinal mucosa. Cancer Chemother. Pharmacol. 11, 167–171 (1983). https://doi.org/10.1007/BF00254198
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00254198