Development of Differentiation-directed Cancer Gene Therapy with p21

• Project/Area Number: 09671310
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Okayama University
• Principal Investigator: HIZUTA Akio Okayama University Medical School, Assistant Professor, 医学部, 講師 (60199007)
• Co-Investigator(Kenkyū-buntansha): FUJIWARA Toshioshi Okayama University Medical School, Instructor, 医学部, 助手 (00304303)
• Project Period (FY): 1997 – 1998
• Project Status: Completed (Fiscal Year 1998)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 1998: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 1997: ¥2,300,000 (Direct Cost: ¥2,300,000)
• Keywords: p21 Gene / Differentiation / Gene Therapy / 老化誘導 / アデノウイルスベクター

Research Abstract

A cycline-dependent kinase inhibitor p21 is induced in thc process of differentiation. To develop a novel gene-based anti-cancer therapy that can induce a welI-differentiated state in cancer cells, we examined antitumor offeet of the p21 gene transfer on human cancer cells. A recombinant adenovirus-mediated transient overexpression of p21 on TE-1 human esophageal cancer cells exhibited morphological changes indicative of differentiation, such as enlarged nuclei and flattened shape. Moreover, expression of involucrin protein, a differentiation marker of squamous cells, was up-regulated after the p21 gene transfer. We also found that retinoic acid receptor (RAR) was positively regulated by the p21 gene transfer in DLD-1 (colon), 1-11299 (lung), H460 (lung), and TE-13 (esophagus) human cancer cell lines. Increased expression of RAR induced the sensitivity to retinoic acid (RA) in RA-resistant DLD-1 cancer cells, resulting in the synergistic antitumor effect of the p21 gene transfer and RA treatment. These observations suggest that adenovirus-mediated p21 gene transfer can induce differentiation in human cancer cells and that the p21 gene has important implications for a differentiation-directed molecular therapy.

Research Products

• [Publications] Kagawa, S.: "p53 expression overcomes p21^<WAF1/CIP1>-mediated G1 arrest and induces apoptosis in human cancer cells." Oncogene. 15. 1903-1909 (1997)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kagawa, S.: "Overexpression of the p21^<sdil> gene induces a senescence-like state in human cancer cells : Implication for senescence-directed molecular therapy for cancer." Cell Death Diff.(in press). (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kagawa, S., Fujiwara, T., Hizuta, A., Yasuda, T., Zhang, W.-W., Roth, J.A., Tanaka, N.: "p53 expression overcomes p21^<WAF1/CIP1>-mediated G1 arrest and induces apoptosis in human cancer cells." Oncogene. 15. 1903-1909 (1997)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kagawa, S., Fujiwara, T., Kadowaki, Y., Hizuta, A., Roth, J.A., Tanaka, N.: "Overexpression of the p21^<sdi 1> gene induces a senescence-like state in human cancer cells : Implication for senescence-directed molecular therapy for cancer." Cell Death Diff.(in press). (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kagawa, S.: "p53 expression overcomes p21^<WAF1/CIP1_>mediated G1 arrest and induces apoptosis in human cancer cells." Oncogene. 15. 1903-1909 (1999)
• [Publications] Kagawa, S.: "Overexpression of the p21^<Si1> gene induces a senescence-lile sta in human cancer cells : Implication for senescence-directed mole cular therapy for cancer." Cell Death Diff.in press. (1999)
• [Publications] 藤原俊義、香川俊輔、田中紀章: "p21^<WAF1/CIP1/SDI1>遺伝子の機能解析." 最新医学. 52. 265-269 (1997)
• [Publications] Kagawa S, Fujiwara T, Hizuta A, Yasuda T, et al: "p53 expression overcomes p21^<AF1/CIP1>-mediated G1 arrest and induces apoptosis in human cancer cells" Oncogene. 15. 1903-1910 (1997)