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Modulation of Proliferation Kinetics in Human Squamous Cell Carcinomas of the Head and Neck

Modulation of Proliferation Kinetics in Human Squamous Cell Carcinomas of the Head and Neck Abstract • Objective. —Proliferation of tumor clonogens during a course of conventional head and neck radiotherapy serves to compromise ultimate tumor control. Biologic strategies that attempt to alter tumor proliferation kinetics using cytostatic or antiproliferative agents may therefore prove valuable by limiting tumor cell repopulation during therapy. Design. —Three human squamous cell carcinoma (SCC) cell lines, derived from primary head and neck cancers, have been characterized in vitro via flow cytometric analysis of proliferation kinetics, and in vivo via tumor xenograft growth evaluation in athymic mice. Results. —The antiproliferative agent α-difluoromethyl-ornithine (DFMO), an inhibitor of polyamine biosynthesis, induced growth inhibition of these SCCs in culture and when administered orally to athymic mice harboring SCC tumor xenografts. Cell cycle kinetic analysis via flow cytometry revealed that DFMO induced a lengthening of in vitro tumor cell potential doubling times. Similarly, DFMO administered continuously via the drinking water to athymic mice harboring human SCC xenografts induced a prolongation of in vivo tumor volume doubling. Conclusions. —These data indicate that biologic agents, such as DFMO, can alter SCC growth kinetics and may prove useful in designing new therapeutic strategies for rapidly proliferating tumors such as those that occur in the head and neck.(Arch Otolaryngol Head Neck Surg. 1993;119:738-742) References 1. Stell PM, Rawson SB. Adjuvant chemotherapy in head and neck cancer . Br J Cancer . 1990;61:779-787.Crossref 2. Begg AC, Hofland I, Van Glabekke M, Bartelink H, Horiot JC. Predictive value of potential doubling time for radiotherapy of head and neck tumor patients: results from the EORTC cooperative trial 22851 . Semin Radiat Oncol. 1992;2:22-25.Crossref 3. Wilson GD, McNally NJ, Dische S, et al. Measurement of cell kinetics in human tumours in vivo using bromodeoxyuridine incorporation and flow cytometry . Br J Cancer . 1988;58:423-431.Crossref 4. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy . Acta Oncol. 1988;27:131-146.Crossref 5. Fowler JF. Potential for increasing the differential response between tumors and normal tissues: can proliferation rate be used? Int J Radiat Oncol Biol Phys. 1986;12:641-645.Crossref 6. Peters LJ, Ang KK, Thames HD. Accelerated fractionation in the radiation treatment of head and neck cancer . Acta Oncol. 1988;27:185-194.Crossref 7. Withers HR. Biologic basis for altered fractionation schemes . Cancer . 1985;55:2086-2095.Crossref 8. Kinsella TJ, Gould MN, Mulcahy RT, Ritter MA, Fowler JF. Integration of cytostatic agents and radiation therapy: a different approach to 'proliferating' human tumors . Int J Radiat Oncol Biol Phys. 191;20:295-302. 9. Verma AK. The enzyme-activated irreversible inhibitor of ornithine decarboxylase, DL-a-difluoromethylornithine: a chemopreventive agent . Prev Med. 1989;18:646-652.Crossref 10. Pegg AE. Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy . Cancer Res. 1988;48:759-774. 11. Garewal HS, Gerner EW, Sampliner R, Kendall D, Alberts DS, Slymen D. Ornithine decarboxylase and polyamine levels in columnar upper gastrointestinal mucosae in patients with Barretts' esophagus . Cancer Res. 1988;48:3288-3291. 12. Luk GD, Baylin SB. Ornithine decarboxylase as a biologic marker in familial colonic polyposis . N Engl J Med. 1984;311:80-83.Crossref 13. Abeloff MD, Rosen ST, Luk GD, Baylin SB, Zeltzman M, Sjoerdsma A. Phase II trials of α-difluoromethylornithine, an inhibitor of polyamine synthesis in advanced small cell lung cancer and colon cancer . Cancer Treat Rep. 1986;70:843-845. 14. Grenman R, Carey TE, McClatchey KD, et al. In vitro radiation resistance among cell lines established from patients with squamous cell carcinoma of the head and neck . Cancer . 1991;67:2741-2747.Crossref 15. Rheinwald JG, Beckett MA. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas . Cancer Res. 1981;41:1657-1663. 16. Allen-Hoffmann BL, Rheinwald JG. Polycyclic aromatic hydrocarbon mutagenesis of human epidermal keratinocytes in culture . Proc Natl Acad Sci U S A. 1984;81:7802-7806.Crossref 17. Begg AC, McNally NJ, Shrieve DC, Karcher H. A method to measure duration of DNA synthesis and the potential doubling time from a single sample . Cytometry . 1985;6:620-626.Crossref 18. Ritter MA, Fowler JF, Kim Y, Lindstrom MJ, Kinsella TJ. Single biopsy, tumor kinetic analyses: a comparison of methods and an extension to shorter sampling intervals . Int J Radiat Oncol Biol Phys. 1992;23:811-820.Crossref 19. Steel GG. Cell proliferation kinetics in tumors . In: Steel GG, Adams GE, Horwich A, eds. The Biological Basis of Radiotherapy . Amsterdam, the Netherlands: Elsevier Science Publishers; 1989:77-88. 20. Phillips RA, Tolmach LG. Repair of potentially lethal damage in X-irradiated HeLa cells . Radiat Res. 1966;29:413-432.Crossref 21. Wallen CA, Ridinger DN, Dethlefsen LA. Heterogeneity of x-ray cytotoxicity in proliferating and quiescent murine mammary carcinoma cells . Cancer Res. 1985;45:3064-3069. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Otolaryngology - Head & Neck Surgery American Medical Association

Modulation of Proliferation Kinetics in Human Squamous Cell Carcinomas of the Head and Neck

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References (23)

Publisher
American Medical Association
Copyright
Copyright © 1993 American Medical Association. All Rights Reserved.
ISSN
0886-4470
eISSN
1538-361X
DOI
10.1001/archotol.1993.01880190034007
Publisher site
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Abstract

Abstract • Objective. —Proliferation of tumor clonogens during a course of conventional head and neck radiotherapy serves to compromise ultimate tumor control. Biologic strategies that attempt to alter tumor proliferation kinetics using cytostatic or antiproliferative agents may therefore prove valuable by limiting tumor cell repopulation during therapy. Design. —Three human squamous cell carcinoma (SCC) cell lines, derived from primary head and neck cancers, have been characterized in vitro via flow cytometric analysis of proliferation kinetics, and in vivo via tumor xenograft growth evaluation in athymic mice. Results. —The antiproliferative agent α-difluoromethyl-ornithine (DFMO), an inhibitor of polyamine biosynthesis, induced growth inhibition of these SCCs in culture and when administered orally to athymic mice harboring SCC tumor xenografts. Cell cycle kinetic analysis via flow cytometry revealed that DFMO induced a lengthening of in vitro tumor cell potential doubling times. Similarly, DFMO administered continuously via the drinking water to athymic mice harboring human SCC xenografts induced a prolongation of in vivo tumor volume doubling. Conclusions. —These data indicate that biologic agents, such as DFMO, can alter SCC growth kinetics and may prove useful in designing new therapeutic strategies for rapidly proliferating tumors such as those that occur in the head and neck.(Arch Otolaryngol Head Neck Surg. 1993;119:738-742) References 1. Stell PM, Rawson SB. Adjuvant chemotherapy in head and neck cancer . Br J Cancer . 1990;61:779-787.Crossref 2. Begg AC, Hofland I, Van Glabekke M, Bartelink H, Horiot JC. Predictive value of potential doubling time for radiotherapy of head and neck tumor patients: results from the EORTC cooperative trial 22851 . Semin Radiat Oncol. 1992;2:22-25.Crossref 3. Wilson GD, McNally NJ, Dische S, et al. Measurement of cell kinetics in human tumours in vivo using bromodeoxyuridine incorporation and flow cytometry . Br J Cancer . 1988;58:423-431.Crossref 4. Withers HR, Taylor JMG, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy . Acta Oncol. 1988;27:131-146.Crossref 5. Fowler JF. Potential for increasing the differential response between tumors and normal tissues: can proliferation rate be used? Int J Radiat Oncol Biol Phys. 1986;12:641-645.Crossref 6. Peters LJ, Ang KK, Thames HD. Accelerated fractionation in the radiation treatment of head and neck cancer . Acta Oncol. 1988;27:185-194.Crossref 7. Withers HR. Biologic basis for altered fractionation schemes . Cancer . 1985;55:2086-2095.Crossref 8. Kinsella TJ, Gould MN, Mulcahy RT, Ritter MA, Fowler JF. Integration of cytostatic agents and radiation therapy: a different approach to 'proliferating' human tumors . Int J Radiat Oncol Biol Phys. 191;20:295-302. 9. Verma AK. The enzyme-activated irreversible inhibitor of ornithine decarboxylase, DL-a-difluoromethylornithine: a chemopreventive agent . Prev Med. 1989;18:646-652.Crossref 10. Pegg AE. Polyamine metabolism and its importance in neoplastic growth and as a target for chemotherapy . Cancer Res. 1988;48:759-774. 11. Garewal HS, Gerner EW, Sampliner R, Kendall D, Alberts DS, Slymen D. Ornithine decarboxylase and polyamine levels in columnar upper gastrointestinal mucosae in patients with Barretts' esophagus . Cancer Res. 1988;48:3288-3291. 12. Luk GD, Baylin SB. Ornithine decarboxylase as a biologic marker in familial colonic polyposis . N Engl J Med. 1984;311:80-83.Crossref 13. Abeloff MD, Rosen ST, Luk GD, Baylin SB, Zeltzman M, Sjoerdsma A. Phase II trials of α-difluoromethylornithine, an inhibitor of polyamine synthesis in advanced small cell lung cancer and colon cancer . Cancer Treat Rep. 1986;70:843-845. 14. Grenman R, Carey TE, McClatchey KD, et al. In vitro radiation resistance among cell lines established from patients with squamous cell carcinoma of the head and neck . Cancer . 1991;67:2741-2747.Crossref 15. Rheinwald JG, Beckett MA. Tumorigenic keratinocyte lines requiring anchorage and fibroblast support cultured from human squamous cell carcinomas . Cancer Res. 1981;41:1657-1663. 16. Allen-Hoffmann BL, Rheinwald JG. Polycyclic aromatic hydrocarbon mutagenesis of human epidermal keratinocytes in culture . Proc Natl Acad Sci U S A. 1984;81:7802-7806.Crossref 17. Begg AC, McNally NJ, Shrieve DC, Karcher H. A method to measure duration of DNA synthesis and the potential doubling time from a single sample . Cytometry . 1985;6:620-626.Crossref 18. Ritter MA, Fowler JF, Kim Y, Lindstrom MJ, Kinsella TJ. Single biopsy, tumor kinetic analyses: a comparison of methods and an extension to shorter sampling intervals . Int J Radiat Oncol Biol Phys. 1992;23:811-820.Crossref 19. Steel GG. Cell proliferation kinetics in tumors . In: Steel GG, Adams GE, Horwich A, eds. The Biological Basis of Radiotherapy . Amsterdam, the Netherlands: Elsevier Science Publishers; 1989:77-88. 20. Phillips RA, Tolmach LG. Repair of potentially lethal damage in X-irradiated HeLa cells . Radiat Res. 1966;29:413-432.Crossref 21. Wallen CA, Ridinger DN, Dethlefsen LA. Heterogeneity of x-ray cytotoxicity in proliferating and quiescent murine mammary carcinoma cells . Cancer Res. 1985;45:3064-3069.

Journal

Archives of Otolaryngology - Head & Neck Surgery – American Medical Association

Published: Jul 1, 1993

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