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Inhibition of myc-dependent breast tumor formation in transgenic mice
Wei Cui1, Barry A Gusterson, A John Clark
1Department of Gene Expression & Development, Roslin Institute, Midlothian, UK.
Abstract:
One of the most promising approaches for cancer gene therapy is the use of the so-called suicide genes, which encode prodrug-activating enzymes and render transduced cells more sensitive to prodrugs. The enzyme nitroreductase (NTR) converts prodrug CB1954 into a cytotoxic DNA interstrand cross-linking agent. We have established transgenic mice in which the pro-oncogene c-myc and NTR were fused to the internal ribosome entry site and coexpressed in luminal cells of the mammary gland under the control of mouse whey acidic protein (WAP) promoter to evaluate NTR mediated ablation of mammary tumors. More than 78% of transgenic females developed in situ or infiltrating carcinomas after three to four pregnancies. By contrast, if the transgenic female mice were given the prodrug CB1954 during their third lactation, the incidence of tumors decreased to less than 40% (P < 0.05). The total number of carcinomas was even more striking with 117 carcinomas identified in 14 non-ablated transgenics compared with only five in 15 treated animals (p < 0.05, student t test). C-myc induced pleomorphic nuclei and mitotic figures were seen as a field change in over 70% of the untreated transgenics compared to 20% in the treated group. Our results suggest that the enzyme pro-drug system NTR-CB1954 efficiently inhibit myc-dependent tumor formation and malignant progression in the mammary gland.
Insights
Cancer gene therapy using nitroreductase (NTR) enzyme and CB1954 prodrug effectively inhibited c-myc-driven mammary tumor formation and progression in mice. This enzyme-prodrug system shows promise for treating specific cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Gene Therapy
Background:
- Cancer gene therapy utilizes suicide genes to activate prodrugs, enhancing cancer cell sensitivity.
- Nitroreductase (NTR) enzyme converts the prodrug CB1954 into a cytotoxic agent.
Purpose of the Study:
- To evaluate the efficacy of the NTR-CB1954 system in inhibiting c-myc-induced mammary tumors in transgenic mice.
- To assess the impact of NTR-mediated ablation on tumor formation and malignant progression.
Main Methods:
- Established transgenic mice coexpressing c-myc and NTR in mammary glands under the WAP promoter.
- Administered prodrug CB1954 to third-lactation transgenic females to induce NTR-mediated tumor ablation.
- Quantified tumor incidence and characterized histological changes.
Main Results:
- Over 78% of untreated transgenic females developed mammary carcinomas after pregnancies.
- CB1954 treatment reduced tumor incidence to less than 40% (P < 0.05).
- Significantly fewer carcinomas (5 vs. 117) and reduced c-myc-induced cellular changes were observed in treated mice.
Conclusions:
- The NTR-CB1954 enzyme-prodrug system efficiently inhibits myc-dependent tumor formation and progression in the mammary gland.
- This approach demonstrates significant therapeutic potential for mammary cancer gene therapy.