Gene therapy utilizing drug resistance genes: A review

Banerjee, Debabrata; Zhao, Shi Cheng; Li, Ming‐Xia ‐X; Schweitzer, Barry; Mineishi, Shin; Bertino, Joseph R.

doi:10.1002/stem.5530120404

Cited by 30 publications

(11 citation statements)

References 54 publications

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“…Information on the difference between wild-type and mutant human TS structures may also be of value in the design of new TS inhibitors with desirable properties. Data presented using DOTAP transduction of mouse marrow cells with the I108A mutant cDNA, encourage the further development of this mutant incorporated into retroviral constructs, to protect hematopoietic progenitor cells from toxic effects of the TS inhibitor raltitrexed (44), now widely used to treat colorectal cancer.…”

Section: Drug-resistant Mutants Of Human Thymidylate Synthasementioning

confidence: 93%

Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis

Tong¹,

Liu-Chen²,

Ercikan-Abali³

et al. 1998

Journal of Biological Chemistry

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Human thymidylate synthase (TS) contains three highly conserved residues Ile-108, Leu-221, and Phe-225 that have been suggested to be important for cofactor and antifolate binding. To elucidate the role of these residues and generate drug-resistant human TS mutants, 14 variants with multiple substitutions of these three hydrophobic residues were created by site-directed mutagenesis and transfected into mouse TS-negative cells for complementation assays and cytotoxicity studies, and the mutant proteins expressed and characterized. The I108A mutant confers resistance to raltitrexed and Thymitaq with respective IC 50 values 54-and 80-fold greater than wild-type but less resistance to BW1843U89 (6-fold). The F225W mutant displays resistance to BW1843U89 (17-fold increase in IC 50 values), but no resistance to raltitrexed and Thymitaq. It also confers 8-fold resistance to fluorodeoxyuridine. Both the kinetic characterization of the altered enzymes and formation of antifolate-resistant colonies in mouse bone marrow cells that express mutant TS are in accord with the IC 50 values for cytotoxicity noted above. The human TS mutants (I108A and F225W), by virtue of their desirable properties, including good catalytic function and resistance to antifolate TS inhibitors, confirm the importance of amino acid residues Ile-108 and Phe-225 in the binding of folate and its analogues. These novel mutants may be useful for gene transfer experiments to protect hematopoietic progenitor cells from the toxic effects of these drugs.Thymidylate synthase (TS), 1 which catalyzes the conversion of dUMP to dTMP, is an attractive target for drug design (1-5). TS inhibitors, which occupy either the substrate or cofactorbinding site, have been designed based on the structure and properties of the enzyme. Fluoropyrimidines, such as 5-fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are metabolized to 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and compete subsequently with the substrate, dUMP, for its binding site and have been used in the clinic for over 40 years to treat breast and gastrointestinal cancers. However, fluoropyrimidines, due to their incorporation into DNA and RNA, are not pure TS inhibitors. Also, they are susceptible to metabolic degradation in vivo. In contrast, the cofactor CH 2 H 4 folate is a relatively large molecule and has a variety of binding sites that may be altered in drug design. In recent years folate analogues have been designed as highly specific and stable TS inhibitors (6). The inhibitor CB3717 was the first folate analogue inhibitor of TS tested in the clinic and although anti-tumor activity was demonstrated, its further development was abandoned due to renal and hepatic toxicity (7,8). The information provided by the crystal structures of TS from bacterial and mammalian sources (9 -18) has led to the design and synthesis of novel analogues of CH 2 H 4 folate, e.g. raltitrexed (Tomudex ® , ZD1694), BW1843U89, Thymitaq (AG337), and AG331 (19 -27). These new and promising agents have entered clinical trials...

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Section: Drug-resistant Mutants Of Human Thymidylate Synthasementioning

confidence: 93%

Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis

Tong¹,

Liu-Chen²,

Ercikan-Abali³

et al. 1998

Journal of Biological Chemistry

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“…[9][10][11] Recently, clinical trials were conducted to investigate the feasibility and safety of retroviral transfer of MDR1 to hematopoietic progenitor cells of cancer patients and reinfusion of transduced cells. [12][13][14][15] The long-term goal of this approach is to achieve safe dose-intensification of drug treatment which may improve the rate of lasting remissions.…”

Section: Introductionmentioning

confidence: 99%

Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice

et al. 2000

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“…[4][5][6][7][8][9][10][11][12] One candi-date gene for chemoprotection is multidrug resistance 1 (MDR1), which encodes a membrane transport glycoprotein able to reduce the intracellular levels of a number of amphiphilic antitumour agents substantially. 4 Transfer and expression of MDR1 in murine and human haemopoietic cells leads to protection against the toxic effects of agents such as vincristine, paclitaxel, colchicine and etoposide.…”

mentioning

confidence: 99%

A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents

et al. 1999

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Gene therapy utilizing drug resistance genes: A review

Cited by 30 publications

References 54 publications

Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis

Probing the Folate-binding Site of Human Thymidylate Synthase by Site-directed Mutagenesis

Drug selection of MDR1-transduced hematopoietic cells ex vivo increases transgene expression and chemoresistance in reconstituted bone marrow in mice

A novel dual function retrovirus expressing multidrug resistance 1 and O6-alkylguanine-DNA-alkyltransferase for engineering resistance of haemopoietic progenitor cells to multiple chemotherapeutic agents

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