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. 1993 Dec;101(Suppl 5):59–65. doi: 10.1289/ehp.93101s559

Concepts, labeling procedures, and design of cell proliferation studies relating to carcinogenesis.

T L Goldsworthy 1, B E Butterworth 1, R R Maronpot 1
PMCID: PMC1519439  PMID: 7912190

Abstract

Chemicals may induce cell proliferation directly as mitogens or indirectly via cell death with subsequent proliferation to replace lost cells. Chemically induced proliferation has been demonstrated to play a role in the carcinogenic process. A wide range of procedures and techniques are currently being used to define the quantitative relationship between the extent and duration of chemically induced cell proliferation and carcinogenic potential in different species and target organs. However, a limited database and nonstandard protocols and procedures for measuring cell proliferation have made it difficult to compare results between laboratories. Comparison of frequencies of S phase between control and treated animals is the most commonly used end point in cell proliferation studies and may be regarded as an indirect indication of a proliferative response. This response can be ascertained as labeling indexes (LI; percentage of cells in S phase) after the administration of the DNA precursor labels (tritiated thymidine; 3H-TdR; bromodeoxyuridine, BrdU) or through immunostaining of the endogenous cell replication marker, proliferating cell nuclear antigen (PCNA). Both approaches are applicable to tissue sections. An important issue in the design of experimental studies for measuring LI is determining how and when to investigate proliferative responses in relation to the chemical treatment regimen. Variables to consider when designing cell proliferation studies include the animal's age, chemical dose and method of treatment, choice and dose of label, time and length that the label is administered, and methods of quantitation.(ABSTRACT TRUNCATED AT 250 WORDS)

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Selected References

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  1. Ames B. N., Gold L. S. Too many rodent carcinogens: mitogenesis increases mutagenesis. Science. 1990 Aug 31;249(4972):970–971. doi: 10.1126/science.2136249. [DOI] [PubMed] [Google Scholar]
  2. Bisconte J. C. Kinetic analysis of cellular populations by means of the quantitative radioautography. Int Rev Cytol. 1979;57:75–126. doi: 10.1016/s0074-7696(08)61462-x. [DOI] [PubMed] [Google Scholar]
  3. Butterworth B. E. Consideration of both genotoxic and nongenotoxic mechanisms in predicting carcinogenic potential. Mutat Res. 1990 Sep;239(2):117–132. doi: 10.1016/0165-1110(90)90033-8. [DOI] [PubMed] [Google Scholar]
  4. Butterworth B. E., Goldsworthy T. L. The role of cell proliferation in multistage carcinogenesis. Proc Soc Exp Biol Med. 1991 Nov;198(2):683–687. doi: 10.3181/00379727-198-43307. [DOI] [PubMed] [Google Scholar]
  5. Butterworth B. E., Popp J. A., Conolly R. B., Goldsworthy T. L. Chemically induced cell proliferation in carcinogenesis. IARC Sci Publ. 1992;(116):279–305. [PubMed] [Google Scholar]
  6. Cattley R. C., Popp J. A. Differences between the promoting activities of the peroxisome proliferator WY-14,643 and phenobarbital in rat liver. Cancer Res. 1989 Jun 15;49(12):3246–3251. [PubMed] [Google Scholar]
  7. Cohen S. M., Ellwein L. B. Cell proliferation in carcinogenesis. Science. 1990 Aug 31;249(4972):1007–1011. doi: 10.1126/science.2204108. [DOI] [PubMed] [Google Scholar]
  8. Columbano A., Ledda-Columbano G. M., Lee G., Rajalakshmi S., Sarma D. S. Inability of mitogen-induced liver hyperplasia to support the induction of enzyme-altered islands induced by liver carcinogens. Cancer Res. 1987 Nov 1;47(21):5557–5559. [PubMed] [Google Scholar]
  9. Eldridge S. R., Goldsworthy T. L., Popp J. A., Butterworth B. E. Mitogenic stimulation of hepatocellular proliferation in rodents following 1,4-dichlorobenzene administration. Carcinogenesis. 1992 Mar;13(3):409–415. doi: 10.1093/carcin/13.3.409. [DOI] [PubMed] [Google Scholar]
  10. Eldridge S. R., Tilbury L. F., Goldsworthy T. L., Butterworth B. E. Measurement of chemically induced cell proliferation in rodent liver and kidney: a comparison of 5-bromo-2'-deoxyuridine and [3H]thymidine administered by injection or osmotic pump. Carcinogenesis. 1990 Dec;11(12):2245–2251. doi: 10.1093/carcin/11.12.2245. [DOI] [PubMed] [Google Scholar]
  11. Farber E. The sequential analysis of liver cancer induction. Biochim Biophys Acta. 1980 May 6;605(2):149–166. doi: 10.1016/0304-419x(80)90002-5. [DOI] [PubMed] [Google Scholar]
  12. Greenwell A., Foley J. F., Maronpot R. R. An enhancement method for immunohistochemical staining of proliferating cell nuclear antigen in archival rodent tissues. Cancer Lett. 1991 Sep;59(3):251–256. doi: 10.1016/0304-3835(91)90149-c. [DOI] [PubMed] [Google Scholar]
  13. Hall P. A., Woods A. L. Immunohistochemical markers of cellular proliferation: achievements, problems and prospects. Cell Tissue Kinet. 1990 Nov;23(6):505–522. doi: 10.1111/j.1365-2184.1990.tb01343.x. [DOI] [PubMed] [Google Scholar]
  14. Haseman J. K. Issues in carcinogenicity testing: dose selection. Fundam Appl Toxicol. 1985 Feb;5(1):66–78. doi: 10.1016/0272-0590(85)90050-8. [DOI] [PubMed] [Google Scholar]
  15. Huff J., Haseman J., Rall D. Scientific concepts, value, and significance of chemical carcinogenesis studies. Annu Rev Pharmacol Toxicol. 1991;31:621–652. doi: 10.1146/annurev.pa.31.040191.003201. [DOI] [PubMed] [Google Scholar]
  16. Jirtle R. L., Meyer S. A. Liver tumor promotion: effect of phenobarbital on EGF and protein kinase C signal transduction and transforming growth factor-beta 1 expression. Dig Dis Sci. 1991 May;36(5):659–668. doi: 10.1007/BF01297035. [DOI] [PubMed] [Google Scholar]
  17. Marsman D. S., Cattley R. C., Conway J. G., Popp J. A. Relationship of hepatic peroxisome proliferation and replicative DNA synthesis to the hepatocarcinogenicity of the peroxisome proliferators di(2-ethylhexyl)phthalate and [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (Wy-14,643) in rats. Cancer Res. 1988 Dec 1;48(23):6739–6744. [PubMed] [Google Scholar]
  18. Maurer H. R. Potential pitfalls of [3H]thymidine techniques to measure cell proliferation. Cell Tissue Kinet. 1981 Mar;14(2):111–120. doi: 10.1111/j.1365-2184.1981.tb00516.x. [DOI] [PubMed] [Google Scholar]
  19. Stanbridge E. J. Identifying tumor suppressor genes in human colorectal cancer. Science. 1990 Jan 5;247(4938):12–13. doi: 10.1126/science.2403692. [DOI] [PubMed] [Google Scholar]
  20. Weghorst C. M., Henneman J. R., Ward J. M. Dose response of hepatic and renal DNA synthetic rates to continuous exposure of bromodeoxyuridine (BrdU) via slow-release pellets or osmotic minipumps in male B6C3F1 mice. J Histochem Cytochem. 1991 Feb;39(2):177–184. doi: 10.1177/39.2.1987261. [DOI] [PubMed] [Google Scholar]
  21. Wilson D. M., Goldsworthy T. L., Popp J. A., Butterworth B. E. Evaluation of genotoxicity, pathological lesions, and cell proliferation in livers of rats and mice treated with furan. Environ Mol Mutagen. 1992;19(3):209–222. doi: 10.1002/em.2850190305. [DOI] [PubMed] [Google Scholar]

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