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VOLUME 13 , ISSUE 3 ( May-June, 2012 ) > List of Articles


The Effects of 5-fluorouracil Alone and in Combination with 13-cis Retinoic Acid and Vitamin D3 on Human Oral Squamous Cell Carcinoma Lines

Zohreh Dalirsani, Safar Farajnia, Yousef Javadzadeh, Masoumeh Mehdipour, Sepideh Koozegari

Citation Information : Dalirsani Z, Farajnia S, Javadzadeh Y, Mehdipour M, Koozegari S. The Effects of 5-fluorouracil Alone and in Combination with 13-cis Retinoic Acid and Vitamin D3 on Human Oral Squamous Cell Carcinoma Lines. J Contemp Dent Pract 2012; 13 (3):345-350.

DOI: 10.5005/jp-journals-10024-1149

License: CC BY-NC 3.0

Published Online: 01-06-2012

Copyright Statement:  Copyright © 2012; Jaypee Brothers Medical Publishers (P) Ltd.



Oral squamous cell carcinoma (OSCC) is responsible for about 90% of oral malignancies and its incidence is increasing. Despite various treatment protocols, survival rate of OSCC is low. Chemotherapy that is used for treating this carcinoma in advanced stages is systemic therapy that destroys carcinogenic cells, and controls tumor metastasis. Chemotherapy is very toxic and has limitations, especially for patients in advanced stages. Considering positive effects of retinoid and vitamin D3 derivatives in treating some carcinomas, we decided to evaluate the effect of combination of these drugs on OSCC. In this study the effects of combination of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 on cultured cell of OSCC have been evaluated.

Materials and methods

OSCC cells were cultured in culture media and different concentration of 5-fluorouracil, 13-cis retinoic acid and vitamin D3 were added to cultured cell as separately and in combinations. The effect of treatment on cell proliferation and induction of apoptosis were evaluated by MTT and TUNEL assays respectively.


Combination of 5-fluorouracil and 13- cis retinoic acid had the highest inhibitory effect on SCC cell proliferation. Combination of two drugs had more apoptotic effect than each of them separately, and combination of three drugs had more effect than combination of two drugs.


Because combination of drugs had more inhibitory effect on cell proliferation than one of them and combination of three drugs had the most apoptotic effect than one of these drugs separately, these drugs may have synergic effect on OSCC.

Clinical significance

Combination of three drugs has more inhibitory effect on cell proliferation and apoptotic effect than one of these drugs.

How to cite this article

Dalirsani Z, Farajnia S, Javadzadeh Y, Mehdipour M, Koozegari S. The Effects of 5-fluorouracil Alone and in Combination with 13-cis Retinoic Acid and Vitamin D3 on Human Oral Squamous Cell Carcinoma Lines. J Contemp Dent Pract 2012;13(3):345-350.

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  1. Utility of metabolic imaging in oral squamous cell carcinoma (SCC) staging. Experience in 30 patients. Clin Positron Imaging 2000 Jul;3(4):171.
  2. Apoptosis of squamous cells at different stages of carcinogenesis following 4-HPR treatment. Carcinogenesis 2002 Mar;23(3):447-56.
  3. Combined and sequential treatment of oral and maxillofacial malignancies: An evolving concept and clinical protocol. Chin Med J (Engl) 2008 Oct 5;121(19):1945-52.
  4. State of the art management of locally advanced head and neck cancer. Br J Cancer 2005 Apr 25;92(8):1341-48.
  5. Inhibition of transcription factor nuclear factor-kappa-B by a mutant inhibitor-kappa-B-alpha attenuates resistance of human head and neck squamous cell carcinoma to TNF-alpha caspase-mediated cell death. Br J Cancer 2000 Nov;83(10):1367-74.
  6. Targeting EGFR and HER-2 with cetuximab-and trastuzumab-mediated immunotherapy in oesophageal squamous cell carcinoma. Br J Cancer 2007 Aug 20;97(4):494-501.
  7. WT1 and BCR-ABL specific small interfering RNA have additive effects in the induction of apoptosis in leukemic cells. Haematologica 2005 Mar;90(3):326-34.
  8. Molecular based treatment of oral cancer. Oral Oncol 2003 Dec;39(8):749-58.
  9. Phase I trial of all-trans retinoic acid in patients with treated head and neck squamous carcinoma. Clin Cancer Res 2000 Mar;6(3):847-54.
  10. Retinoids: Application in premalignant lesions and oral cancer. Med Oral 2001 Mar-Apr;6(2):114-23.
  11. Antisense oligonucleotides and all-trans retinoic acid have a synergistic anti-tumor effect on oral squamous cell carcinoma. BMC Cancer 2008;8:159.
  12. A DNA methyltransferase inhibitor and all-trans retinoic acid reduce oral cavity carcinogenesis induced by the carcinogen 4-nitroquinoline 1-oxide. Cancer Prev Res (Phila) 2009 Dec;2(12):1100-10.
  13. Modulation of growth and proliferation in squamous cell carcinoma by retinoic acid: A rationale for combination therapy with chemotherapeutic agents. Int J Cancer 1995 May 4;61(3):409-15.
  14. Effects of acyclic retinoid on growth, cell cycle control, epidermal growth factor receptor signaling, and gene expression in human squamous cell carcinoma cells. Clin Cancer Res 2004 Feb 1;10(3):1130-40.
  15. In vitro inhibition of prostaglandin biosynthesis in squamous cell carcinoma by retinoids. Eicosanoids 1990;3(2):95-98.
  16. Clinical significance of altered expression of retinoid receptors in oral precancerous and cancerous lesions: Relationship with cell cycle regulators. Int J Cancer. 2006 Mar 1;118(5):1077-89.
  17. Combination of 1-alpha,25-dihydroxyvitamin D3 with dexamethasone enhances cell cycle arrest and apoptosis: Role of nuclear receptor cross-talk and Erk/Akt signaling. Clin Cancer Res 2001 Dec;7(12):4164-73.
  18. Antiproliferative effects of 1 alpha, 25-dihydroxyvitamin D3 and vitamin D analogs on tumor-derived endothelial cells. Endocrinology 2002 Jul;143(7):2508-14.
  19. Treatment with 1-alpha, 25-dihydroxyvitamin D3 (vitamin D3) to inhibit carcinogenesis in the hamster buccal pouch model. Arch Otolaryngol Head Neck Surg 2007 Nov;133(11):1149-52.
  20. 1,25(OH)2 vitamin D3 induces elevated expression of the cell cycle-regulating genes P21 and P27 in squamous carcinoma cell lines of the head and neck. Acta Otolaryngol 2001 Jan;121(1):103-09.
  21. 1,25(OH)2 Vitamin D3 induces elevated expression of the cell cycle inhibitor p18 in a squamous cell carcinoma cell line of the head and neck. J Oral Pathol Med 2006 Sep;35(8):472-78.
  22. Antitumor effects of two less-calcemic vitamin D analogs (Paricalcitol and QW-1624F2-2) in squamous cell carcinoma cells. Oncology 2006;70(6):483-92.
  23. Calcipotriol (MC 903), a synthetic derivative of vitamin D3 stimulates differentiation of squamous carcinoma cell line in the raft culture. Anticancer Res 1996 Jan-Feb;16(1):337-47.
  24. Squamous carcinoma cell lines fail to respond to 1,25-Dihydroxyvitamin D despite normal levels of the vitamin D receptor. J Invest Dermatol 1996 Mar;106(3):522-25.
  25. Dietary vitamin D and cancers of the oral cavity and esophagus. Ann Oncol 2009 Sep;20(9):1576-81.
  26. Serum 25(OH)-vitamin D concentration and risk of esophageal squamous dysplasia. Cancer Epidemiol Biomarkers Prev 2007 Sep;16(9):1889-93.
  27. Retinoic acid and interferon alpha act synergistically as antiangiogenic and antitumor agents against human head and neck squamous cell carcinoma. Cancer Res 1998 Dec 1;58(23):5551-58.
  28. In vitro inhibition of head and neck cancer-cell growth by human recombinant interferon-alpha and 13-cis retinoic acid. Br J Biomed Sci 2001;58(4):226-29.
  29. Induction of cell cycle arrest and apoptosis by a combined treatment with 13-cis-retinoic acid, interferon-alpha-2a, and alpha-tocopherol in squamous cell carcinoma of the head and neck. Head Neck 2007 Apr;29(4):351-61.
  30. Potentiation of cisplatin antitumor activity using a vitamin D analogue in a murine squamous cell carcinoma model system. Cancer Res 1997 Sep 1;57(17):3759-64.
  31. 1-alpha,25-Dihydroxyvitamin D3 potentiates cisplatin antitumor activity by p73 induction in a squamous cell carcinoma model. Mol Cancer Ther 2008 Sep;7(9):3047-55.
  32. Enhanced antitumor efficacy of cisplatin in combination with ALRT1057 (9-cis retinoic acid) in human oral squamous carcinoma xenografts in nude mice. Clin Cancer Res 1996 Mar;2(3):511-20.
  33. The independent and combined effects of RAR-, RXR-, and VDR-selective ligands on the growth of squamous cell carcinoma in vitro. J Otolaryngol 1999 Apr;28(2):83-89.
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