| RRC ID |
36766
|
| 著者 |
Mabuchi M, Shimizu T, Ueda M, Sasakawa Y, Nakao S, Ueda Y, Kawamura A, Tsujikawa K, Tanaka A.
|
| タイトル |
Improving the bioavailability and anticancer effect of the PCA-1/ALKBH3 inhibitor HUHS015 using sodium salt.
|
| ジャーナル |
In Vivo
|
| Abstract |
Prostate cancer antigen (PCA)-1/AlkB homologue 3 (ALKBH3) has been identified as a clinically significant factor and siRNA of PCA-1 inhibits DU145 proliferation both in vitro and in vivo. HUHS015 ( 1: ), a previous reported PCA-1 small-molecule inhibitor, was also effective without any obvious side-effects or toxicity. The potency of HUHS015, however, is not satisfying. We thought the reason is poor solubility of HUHS015 because insoluble material remained at the injection site after subcutaneous administration. To improve this inhibitor's solubility, we prepared various salts of HUHS015 and examined their solubility, which resulted in the selection of HUHS015 sodium salt ( 2: ) for further studies in vivo. Next, we compared the pharmacokinetics of 1: and 2: via several administration routes. We observed significant improvements in the pharmacokinetic parameters. For example, subcutaneous administration of 2: increased the area under the curve (AUC)0-24 by 8-fold compared to 1 and increased the suppressive effect on the proliferation of DU145 cells in a xenograft model.
|
| 巻・号 |
29(1)
|
| ページ |
39-43
|
| 公開日 |
2015-1-1
|
| PII |
29/1/39
|
| PMID |
25600528
|
| MeSH |
Administration, Intravenous
Administration, Oral
AlkB Homolog 3, Alpha-Ketoglutarate-Dependent Dioxygenase
Animals
Antigens, Neoplasm
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics*
Benzimidazoles / administration & dosage
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Biological Availability
Cell Line, Tumor
DNA Repair Enzymes / antagonists & inhibitors*
Dioxygenases / antagonists & inhibitors*
Disease Models, Animal
Humans
Infusions, Parenteral
Male
Prostatic Neoplasms / drug therapy
Prostatic Neoplasms / metabolism
Prostatic Neoplasms / pathology
Pyrazoles / administration & dosage
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Rats
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
|
| IF |
1.541
|
| 引用数 |
4
|
|
WOS 分野
|
MEDICINE, RESEARCH & EXPERIMENTAL
|
| リソース情報 |
| ヒト・動物細胞 |
DU145(RCB2143) |
