Аntimetastatic activity of the phenylsulfonyl-L-proline derivative AL-828, a matrix metalloproteinase-2 inhibitor, in a male C57BL/6 mouse model of Lewis lung carcinoma

Background. Matrix metalloproteinases (MMPs) are a group of zinc dependent enzymes that play a key role in regulating both physiological and pathological processes in humans, particularly in oncological diseases. MMP-2 (gelatinase A) overexpression promotes metastatic progression in tumor cells. The development of selective MMP inhibitors as anticancer agents represents a promising approach in modern pharmacology. Previously, the compound 1-({4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl)-L-proline, which received the laboratory code AL-828, was designed and synthesized using the pharmacophoric approach, possessing inhibitory activity against MMP-2.
Objective. Antitumor and antimetastatic activity of AL-828 compared with gemcitabine as the first-line antitumor drug.
Methods. This study was conducted on an experimental model of Lewis lung carcinoma (LLC) in C57BL/6 mice. AL-828 was administered intraperitoneally (i.p.) at doses of 10 and 30 mg/kg from day 1 to day 14 of tumor development. The antitumor drug gemcitabine was administered intraperitoneally as a reference drug at a dose of 50 mg/kg on days 2 and 9 of tumor development. The antitumor effect was assessed on days 7, 9, 15, and 21 of tumor development, and the metastasis inhibition index (MII) was measured on day 21 of tumor development. In this study, the average lifespan and survival rates were measured. Survival analysis was performed using the Kaplan–Meier method.
Results. AL-828 at doses of 10 and 30 mg/kg did not cause inhibition of tumor growth (ITG), whereas gemcitabine at a dose of 50 mg/kg significantly reduced tumor growth at all stages of registration at the level of 60 %. AL- 828 at a doses of 10 and 30 mg/kg, AL-828 showed antimetastatic effects, with MII values of 48.3 % and 39.2 %, respectively. Gemcitabine showed an MII of 75.8 %. Lungs from 50 % of the control group exhibited both light and high colonization potential with metastases. In contrast, the administration of either gemcitabine or AL-828 resulted in only light colonization potential in 90 % of treated animals.
Conclusion. Systemic course administration of AL-828 demonstrated antimetastatic activity in a model of LLC.

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