Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:3.5.4.1 (
cytosine deaminase
)
747
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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 prodrug-enzyme combination for the treatment of this disease. Paclitaxel (Taxol;
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.
...
PMID:Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer? 1828 24
