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In vitro evaluation of novel SN-38 prodrug activated by α-rhamnosidase of exogenous enzyme.
- Source :
-
Analytical sciences : the international journal of the Japan Society for Analytical Chemistry [Anal Sci] 2024 Aug; Vol. 40 (8), pp. 1529-1535. Date of Electronic Publication: 2024 May 15. - Publication Year :
- 2024
-
Abstract
- This study introduces the α-rhamnose (Rham)-conjugated prodrug of SN-38 (Rham-SN-38) as a promising alternative to irinotecan. α-rhamnosidase, responsible for SN-38 release from Rham-SN-38, does not express in human cells, minimizing individual variability and side effects. The injection of the α-rhamnosidase into the tumor tissues makes it possible, for the first time, to activate the Rham-SN-38. Furthermore, α-rhamnosidase demonstrates significantly higher activity than carboxylesterase, the specific enzyme activating irinotecan. SN-38 release mediated by α-rhamnosidase completes within 2 h, with a k <subscript>cat</subscript> /K <subscript>m</subscript> value approximately 5.0 × 10 <superscript>4</superscript> -fold higher than that of irinotecan. The 50% inhibition concentration (IC <subscript>50</subscript> ) of Rham-SN-38 against three types of cancer cells and one normal cell exceeds 4.5 × 10 <superscript>3</superscript>  nM. The addition of α-rhamnosidase significantly increases cytotoxicity, with IC <subscript>50</subscript> comparable to free SN-38. The QIC <subscript>50</subscript> , an index reflecting the difference in cytotoxicity with and without α-rhamnosidase, exceeds approximately 1.0 × 10 <superscript>2</superscript> -fold. Rham-SN-38, synthesized in this study, demonstrates significant potential as a prodrug for cancer therapy.<br /> (© 2024. The Author(s), under exclusive licence to The Japan Society for Analytical Chemistry.)
- Subjects :
- Humans
Drug Screening Assays, Antitumor
Dose-Response Relationship, Drug
Cell Line, Tumor
Irinotecan pharmacology
Irinotecan chemistry
Prodrugs pharmacology
Prodrugs chemistry
Prodrugs metabolism
Prodrugs chemical synthesis
Glycoside Hydrolases metabolism
Glycoside Hydrolases antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1348-2246
- Volume :
- 40
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Analytical sciences : the international journal of the Japan Society for Analytical Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 38748393
- Full Text :
- https://doi.org/10.1007/s44211-024-00593-9