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Genetically Modified DR5-Specific TRAIL Variant DR5-B Revealed Dual Antitumor and Protumoral Effect in Colon Cancer Xenografts and an Improved Pharmacokinetic Profile.
Yagolovich, Anne V; Artykov, Artem A; Karmakova, Tatiana A; Vorontsova, Maria S; Pankratov, Andrey A; Andreev-Andrievsky, Alexander A; Dolgikh, Dmitry A; Kirpichnikov, Mikhail P; Gasparian, Marine E.
Afiliação
  • Yagolovich AV; Department of Bioengineering, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Artykov AA; Department of Bioengineering, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Karmakova TA; Department of modifiers and protectors of antitumor therapy, National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Moscow, Russia.
  • Vorontsova MS; Department of modifiers and protectors of antitumor therapy, National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Moscow, Russia.
  • Pankratov AA; Department of modifiers and protectors of antitumor therapy, National Medical Research Radiological Center of the Ministry of Health of the Russian Federation, Moscow, Russia.
  • Andreev-Andrievsky AA; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Dolgikh DA; Department of Bioengineering, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Kirpichnikov MP; Department of Bioengineering, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia; Faculty of Biology, Lomonosov Moscow State University, Moscow, Russia.
  • Gasparian ME; Department of Bioengineering, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia. Electronic address: marine_gasparian@yahoo.com.
Transl Oncol ; 13(4): 100762, 2020 Apr.
Article em En | MEDLINE | ID: mdl-32224450
Despite the weak clinical efficacy of TRAIL death receptor agonists, a search is under way for new agents that more efficiently activate apoptotic signaling. We previously created a TRAIL DR5-selective variant DR5-B without affinity for the DR4, DcR1, DcR2, and OPG receptors and increased proapoptotic activity in tumor cells. Here we showed that DR5-B significantly inhibited tumor growth in HCT116 and Caco-2 but not in HT-29 xenografts. The antitumor activity of DR5-B was 2.5 times higher in HCT116 xenografts compared to TRAIL. DR5-B at a dose of 2 or 10 mg/kg/d for 10 days inhibited tumor growth in HCT116 xenografts by 26% or 50% respectively, and increased animal survival. Unexpectedly, DR5-B at a higher dose (25 mg/kg/d) inhibited tumor growth only during the first 8 days of drug exposure, while at the end of the monitoring, no effect or even slight stimulation of tumor growth was observed. The pharmacokinetic parameters of DR5-B were comparable to those of TRAIL, except that the half-life was 3.5 times higher. Thus, enhancing TRAIL selectivity to DR5 may increase both antitumor and proliferative activities depending on the concentration and administration regimens.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: Transl Oncol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Federação Russa

Texto completo: 1 Base de dados: MEDLINE Idioma: En Revista: Transl Oncol Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Federação Russa