Genz-644282, identified as a potent topoisomerase I inhibitor, demonstrates significant efficacy across a spectrum of 29 human tumor cell lines with IC50 values ranging from 1.8 nM to 1.8 μM[1]. Genz-644282 exhibits substantial suppressive effects on the PPTP cell lines, with IC50 values between 0.2-21.9 nM and an average IC50 of 1.2 nM[2]. Furthermore, Genz-644282 is effective in stabilizing Top1-DNA covalent cleavage complexes, and at 0.1 μM, it induces γH2AX foci in both human colon cancer HCT116 cells and breast cancer MCF7 cells, demonstrating cytotoxicity in CPT-resistant human cancer cell lines[3].
体内研究
When administered intravenously to mice, Genz-644282 at doses of 1-4 mg/kg induces notable tumor growth delay (TGD) across various human cancer xenograft models, including colon cancer, non-small cell lung carcinoma, and melanoma. Specifically, it achieves a TGD ranging from 14 to 34 days in these models, with the extent of delay varying based on the type of tumor and the dosage administered[1].
At Genz644282's maximum tolerated dose (MTD) of 4 mg/kg, Genz644282 secures maintained complete responses (MCR) in all evaluated solid tumor models (6/6). At a dose of 2 mg/kg, it induces complete responses (CR) or MCR in all tested tumor models (3/3), leading to objective regressions in 41% (7 of 17) of the models, while no objective responses are observed at a dose of 1 mg/kg[2].
体外研究
Genz-644282, identified as a potent topoisomerase I inhibitor, demonstrates significant efficacy across a spectrum of 29 human tumor cell lines with IC50 values ranging from 1.8 nM to 1.8 μM[1].
Genz-644282 exhibits substantial suppressive effects on the PPTP cell lines, with IC50 values between 0.2-21.9 nM and an average IC50 of 1.2 nM[2].
Furthermore, Genz-644282 is effective in stabilizing Top1-DNA covalent cleavage complexes, and at 0.1 μM, it induces γH2AX foci in both human colon cancer HCT116 cells and breast cancer MCF7 cells, demonstrating cytotoxicity in CPT-resistant human cancer cell lines[3].
Genz-644282 细胞实验
Cell Line
Concentration
Treated Time
Description
References
GL261 murine glioma cells
1 or 100 nM
6 hours
To assess whether The-0504 induces DNA double-strand breaks, results showed that γH2AX expression increases up to 2-fold compared to control
Cell Death Dis. 2024 Apr 13;15(4):262
U-87 MG human glioblastoma cells
1-100 nM
48 hours
To assess the effect of The-0504 on cell viability, results showed that The-0504 decreases cell viability in a concentration-dependent fashion with an IC50 of about 100 nM
Cell Death Dis. 2024 Apr 13;15(4):262
GL261 murine glioma cells
1-100 nM
48 hours
To assess the effect of The-0504 on cell viability, results showed that The-0504 decreases cell viability in a concentration-dependent fashion with an IC50 of about 100 nM
Cell Death Dis. 2024 Apr 13;15(4):262
MiaPaca2 cells
1 μM
6 hours
To assess the expression of the DNA double-strand break marker γH2AX. The-0504 induced more pronounced and persistent γH2AX phosphorylation compared to free Genz-644282.
Heliyon. 2023 Oct 6;9(10):e20770
CPT-K5 cells (carrying D533G mutation in TOP1 gene)
0.1 μM and 1 μM
4 and 24 hours
Evaluated cytotoxicity of Genz-644282 against CPT-resistant cell lines, finding Genz only slightly induced DSB formation at 1 μM, indicating D533G mutation confers Genz resistance.
J Exp Clin Cancer Res. 2021 Feb 10;40(1):63
CEM/C2 cells (carrying N722S mutation in TOP1 gene)
1 μM
4 and 24 hours
Evaluated cytotoxicity of Genz-644282 against CPT-resistant cell lines, finding Genz effectively induced DSB formation while CPT did not.
J Exp Clin Cancer Res. 2021 Feb 10;40(1):63
SV40-transformed MRC5 cells
1 μM
4 and 24 hours
Investigated the mechanism of Genz-644282-induced double-strand breaks (DSBs) formation, finding early response dependent on TOP1 function but not MUS81–EME1/2 function, while late response required both functions.
J Exp Clin Cancer Res. 2021 Feb 10;40(1):63
Genz-644282 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6N mice
GL261 glioma model
Intranasal or intravenous
0.3 mg/kg or 0.9 mg/kg (intranasal); 2.0 mg/kg (intravenous)
Every two days for 2 weeks (six times)
To evaluate the effect of The-0504 on glioma volume and survival rate, results showed that intranasal administration reduced tumor volume by more than 70%, intravenous administration reduced it by 53%, and intranasal administration significantly improved survival rate
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