5’-S-(3-aminophenyl)-5’-thioadenosine, a novel chemoprotective agent for reducing toxic side effects of fluorouracil in treatment of MTAP-deficient cancers
crossref(2024)
摘要
Background Nucleobase analogue (NBA) drugs are effective chemotherapeutics, but their clinical use is limited by severe side effects. Compelling evidence suggests the use of S -methyl-5’-thioadenosine (MTA) can selectively reduce NBA toxicity on normal tissues while maintaining the efficacy of NBAs on methylthioadenosine phosphorylase (MTAP)-deficient cancers. However, we found that MTA induced hypothermia at its effective dose, limiting its translational potential. We intended to find an MTA analogue that can exert MTA function while minimize the undesired side effects of MTA. Thus, such an analogue can be used in combination with NBAs in selectively targeting MTAP-deficient cancers.
Methods We screened a library of MTA analogues for the following criteria: 1) being substrates of MTAP; 2) selectively protection on MTAP-expressing cells from NBA toxicity using MTAP -isogenic cell lines; 3) ability to protect the host from NBA toxicity without hypothermic effect; and 4) lack of interference on the tumor-suppressive effect of NBA in mice bearing MTAP-deficient tumors.
Results We identified 5’- S -(3-aminophenyl)-5’-thioadenosine (m-APTA) that did not induce hypothermia at the effective doses. We demonstrated that m-APTA could be converted to adenine by MTAP. Consequently, m-APTA selectively protected mouse hosts from 5-FU-induced toxicity (i.e. anemia); yet it did not interfere with the drug efficacy on MTAP-deficient bladder cancers. In silico docking studies revealed that, unlike MTA, m-APTA interact inefficiently with adenosine A1 receptor, providing a plausible explanation of the superior safety profile of m-APTA.
Conclusion m-APTA can significantly improve the translational potential of the NBA toxicity reduction strategy in selectively targeting MTAP-deficient cancers.
### Competing Interest Statement
The authors have declared no competing interest.
* 2-FA
: 2-fluoroadenine
5-FU
: 5-florouracial
5’-dAdo
: 5’-deoxyadenosine
6-TG
: 6-thioguanine (6-TG)
A1R
: Adenosine A1 receptor
i.p.
: Intraperitoneal
m-APTA
: 5’- S -(4-aminophenyl)-5’-thioadenosine
MTA
: S -methyl-5’-thioadenosine
MTAP
: Methylthioadenosine phosphorylase
NBA
: Nucleobase analogue
p-APTA
: 5’- S -(4-aminophenyl)-5’-thioadenosine
PDX
: Patient-derived xenograft
PRPP
: Phosphoribosyl-5-pyrophosphate
PTA
: Phenylthioadenosine
RBC
: Red blood cell
XO
: Xanthine oxidase
更多查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要