Skip to main content
SpringerLink
Log in

Sequence-dependent toxicity and small bowel mucosal injury in neonatal mice treated with low doses of 5-azacytidine and X-irradiation at the late organogenesis stage

  • Published:
Radiation and Environmental Biophysics Aims and scope Submit manuscript

Summary

A combined treatment of pregnant mice on day 12 of gestation with both azacytidine and X-irradiation in low doses induces sequence-dependent histological effects. These effects, in turn, induce different symptomatic signs if evaluated either prenatally or neonatally. In the azacytidine treatment/X-irradiation sequence the malformations of the fetal forebrain are predominant. Consequently, these dams show a high incidence in the stillbirth rate. Conversely, the X-irradiation/azacytidine treatment schedule leads only to a mild brain hypoplasia, and does not cause an increased stillbirth rate. In these offspring, however, a severe impairment of small bowel epithelial proliferation capacity was found. This is linked to an outstanding neonatal mortality within 48 h after birth. The pathogenesis of these sequence-dependent effects can be attributed to a selective vulnerability of cells in different stages of the generation cycle. This comprises a high degree of cytolethality affecting the S/G2-stage cells in azacytidine/X-irradiation treatment and the G1/S-stage cells in the reverse combinations (Schmahl 1979). The present observations show the validity of a teratological assay in providing a detailed analysis of the cell kinetic responses after combined noxious influences.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Bertram JS, Heidelberger C (1974) Cell cycle dependency of oncogenic transformation induced by nitrosoguanidine in culture. Cancer Res 34: 524–537

    Google Scholar 

  • Dewey WC, Stone LE, Miller HH, Giblak RE (1971) Radiosensitization with 5-bromo-deoxyuridine of Chinese Hamster cells X-irradiated during different phases of the cell cycle. Radiat Res 47: 672–688

    Google Scholar 

  • Griem ML, Ranninger K (1962) Modification of the radiation effect on hair roots of the mouse by actinomycin. Radiat Res 17:92–100

    Google Scholar 

  • Kauffman SL (1968) Lengthening of the generation cycle during embryonic differentiation of the mouse neural tube. Exp Cell Res 49: 420–424

    Google Scholar 

  • Kauffman SL (1975) Kinetics of pulmonary epithelial proliferation during prenatal growth of the mouse lung. Anat Res 183: 393–404

    Google Scholar 

  • Li LH, Olin R, Fraser TJ, Bhuyan BK (1970) Phase specificity of 5-azacytidine against mammalian cells in tissue culture. Cancer Res 30: 2770–2775

    Google Scholar 

  • Lloyd HH, Dulmadge EA, Willkoff LJ (1972) Kinetics of the reduction in viability of cultured L 1210 leukemia cells exposed to 5-azacytidine. Cancer Chemother Rep 56: 585–591

    Google Scholar 

  • Millar JL, Hudspith BN (1976) Sparing effect of cyclophosphamide pretreatment on animals lethally treated with X-irradiation. Cancer Treat Rep 60: 409–414

    Google Scholar 

  • Miltenberger HG, Korte A (1976) Über die gleichzeitige Wirkung von ionisierender Strahlung und chemischen Agentien auf tierische Zellen. Drug Res 26: 1303–1307

    Google Scholar 

  • Paterson ARP, Jakobs ES, Lauson GJ, Weinstein WM (1979) Drug sequence-dependent toxicity and small bowel mucosal injury in mice treated with low doses of 3-deazauridine and arabinofuranosylcytosine. Cancer Res 39: 2216–2219

    Google Scholar 

  • Phelps TA, Blackett NM (1979) Protection of intestinal damage by pretreatment with cytarabine. Int J Radiat Oncol Biol Phys 5: 1617–1620

    Google Scholar 

  • Phillips TL, Sharan MD, Margolis LW (1975) Modification of radiation injury to normal tissues by chemotherapeutic agents. Cancer 35: 1676–1684

    Google Scholar 

  • Raake W, Tempel K, Hollatz R (1977) Zur Wirkung von 6-Methyluracil auf Mäuse nach Schädigung durch 2,4,6-Triäthylenimino-1,3,5-triazin oder Ràntgenbestrahlung. Drug Res 27: 132–137

    Google Scholar 

  • Raedler A, Sievers J (1975) The development of the visual system of the albino rat. Adv Anat Embryol Cell Biol 50:1–88

    Google Scholar 

  • Schenken LL, Burholt DR, Hagemann RF, Lesher S (1976) The modification of gastrointestinal tolerance and responses to abdominal irradiation by chemotherapeutic agents. Radiology 120: 417–420

    Google Scholar 

  • Schmahl W (1979) Different teratogenic efficacy to mouse fetal CNS of 5-azacytidine in combination with X-irradiatioin depends on the sequence of successive application. Teratology 19: 63–70

    Google Scholar 

  • Schmahl W (1982) Kinetics of telecephalic neural cell proliferation during the fetal regeneration period following a single X-irradiation at the late organogenesis stage. I. Sequential study of cell kinetics during the phase of acute events. Radiat Environ Biophys 21: 19–31

    Google Scholar 

  • Schultze B, Nowak B, Maurer W (1974) Cycle times of the neural epithelial cells of various types of neuron in the rat. An autoradiograpohic study. J Comp Neurol 158: 207–218

    Google Scholar 

  • Seifertova M, Vesely J, Cihak A (1974) Localization of the labelled 5-azacytidine in cultured mouse embryonic cells. Experientia 30: 1463–1465

    Google Scholar 

  • Seifertova M, Vesely J, Cihak A, Sorm F (1972) Pycnotic degeneration of ventricular cells in embryonic brain following transplacental exposure to 5-azacytidine. Experientia 28: 841–842

    Google Scholar 

  • Smith WW, Carter SK, Wilson SM, Newman JW, Cornfield J (1970) Joint lethal effects of actinomycin D and radiation in mice. Cancer Res 30: 51–57

    Google Scholar 

  • Tolmach LJ, Weiss BG, Hopwood LE (1971) Ionizing radiations and the cell cycle. Fed Proc 30: 1742–1751

    Google Scholar 

  • Tsubouchi S, Matsuzawa T (1974) Rapid radiation cell death and cell proliferation in intestinal epithelium after 1000 rad irradiation. Radiat Res 57:451–458

    Google Scholar 

  • UNSCEAR (1982) “Biological effects of radiation in combination with other physical, chemical or biological agents” pg 727–773. Report of the United Nations Scientific Committe on the Effects of Atomic Radiation. Official Record of the General Assembly, 37th Session, Supplement No. 45 (A/37/45). United Nations, New York

    Google Scholar 

  • Vesely J, Gostof R, Cihak A, Sorm F (1969) Radioprotective effect of 5-azacytidine in AKR mice. Z Naturforsch 24: 318–320

    Google Scholar 

  • Vesselinovitch SC, Simmons EL, Mihailovich N, Lombard LS, Rav KVN (1972) Additive leukemogenicity of urethan and X-irradiation in infant and young adult mice. Cancer Res 32: 222–225

    Google Scholar 

  • Withers HR, Elkind MM (1970) Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int J Radiat Biol 17: 261–267

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Abteilung Nuklearbiologie der Gesellschaft für Strahlen- und Umweltforschung mbH München, D-8042, Neuherberg, Federal Republic of Germany

    W. Schmahl

Authors
  1. W. Schmahl
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schmahl, W. Sequence-dependent toxicity and small bowel mucosal injury in neonatal mice treated with low doses of 5-azacytidine and X-irradiation at the late organogenesis stage. Radiat Environ Biophys 21, 235–245 (1983). https://doi.org/10.1007/BF01341460

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01341460

Keywords

Search

Navigation