Gene Directed Enzyme Prodrug Therapy for Ovarian Cancer: Could GDEPT Become a Promising Treatment Against Ovarian Cancer?

ISSN: 1875-5992 (Online)
ISSN: 1871-5206 (Print)

Volume 17, 14 Issues, 2017

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Anti-Cancer Agents in Medicinal Chemistry

Formerly: Current Medicinal Chemistry - Anti-Cancer Agents

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Michelle Prudhomme
Institut de Chimie de Clermont-Ferrand
Université Clermont Auvergne

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Gene Directed Enzyme Prodrug Therapy for Ovarian Cancer: Could GDEPT Become a Promising Treatment Against Ovarian Cancer?

Anti-Cancer Agents in Medicinal Chemistry, 8(2): 232-239.

Author(s): Akihiro Nawa, Tadatoshi Tanino, Chen Hong Luo, Masahiro Iwaki, Hiroaki Kajiyama, Kiyosumi Shibata, Eiko Yamamoto, Kazuhiko Ino, Yukihiro Nishiyama and Fumitaka Kikkawa.

Affiliation: Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya 466-8550, Japan.


Gene-directed enzyme prodrug therapy (GDEPT) involves the treatment concept of having maximal efficacy and minimal adverse effects. Several GDEPT strategies have been developed combining cytosine deaminase and 5-fluorocytosine, cytochrome P450 2B1 and cyclophosphamide, and carboxylesterase (CES) and irinotecan in experimental models. The active forms of these prodrugs, however, are not a frontline therapy for the treatment of ovarian cancer. It would be beneficial to develop a more effective prodrugenzyme combination for the treatment of this disease. Paclitaxel (TaxolR; TAX) is currently one of the most important anti-cancer drugs in chemotherapy of ovarian cancer. One of TAX prodrugs, 2-ethylcarbonate-linked paclitaxel (TAX-2-Et), was generated and examined regarding its pharmacological aspects. The prodrug of TAX-2-Et converts into active form TAX by carboxylesterase (CES). TAX-2-Et did not exhibit polarized transport in the Caco-2 cells expressing P-glycoprotein (P-gp) in the absence or presence of verapamil which is a inhibitor of P-gp, suggesting that TAX-2-Et is not a target of P-gp like TAX and rhodamine123. Moreover, SKOV3/TAX60 cells which are overexpressing P-gp did not also exhibit any change in cellular uptake of TAX-2-Et regardless of the absence or presence of verapamil. Consequently, the uptake of TAX-2-Et into the TAX-resistant cells was quantitatively similar to that internalized in the parental SKOV3 cells which are P-gp-negative. In the CES-transfected SKOV3 cells, the EC50 value of TAX (10.6 nM) was approximately 4-fold higher than that of TAX-2-Et (2.5 nM). We herein provide evidence that TAX-2-Et could circumvent P-gp-associated cellular efflux of TAX, suggesting that this combination therapy is a potential GDEPT strategy for ovarian cancer in the future. Finally, this review focuses on the development, application and potential of various GDEPTs for treating ovarian cancer, and the scope and progress of new GDEPTs are discussed.


Carboxylesterase, 2'-ethylcarbonate-linked paclitaxel, gene directed enzyme prodrug therapy, P-glycoprotein, intraperitoneal administration, ovarian cancer, paclitaxel, virotherapy.

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Article Details

Volume: 8
Issue Number: 2
First Page: 232
Last Page: 239
Page Count: 8
DOI: 10.2174/187152008783497000
Price: $58
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