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Antitumor activity of new chemical compounds in triple negative mammary adenocarcinoma models.

ABSTRACT: Aim:According to the need for the development of new anticancer agents, we have synthetized novel bioactive compounds and aimed to determine their antitumor action. Materials & methods:We describe in vitro studies evaluating the effect of 35 novel chemical compounds on two triple negative murine mammary adenocarcinoma tumors. Results & conclusion:Three compounds were selected because of their high antitumor activity and their low toxicity to normal cells. Their effect on tumor cells apoptosis, clonogenicity and migratory capacity, were determined. We found that the selected compounds showed inhibition of viability and clonogenic capacity, and promotion of apoptosis. They also decreased the migratory capacity of tumor cells. The results obtained suggest the likelihood of their future use as antitumor and/or antimetastatic agents.

SUBMITTER: Giolito MV

PROVIDER: S-EPMC7050605 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Antitumor activity of new chemical compounds in triple negative mammary adenocarcinoma models.

Giolito María V MV Camacho Cristian M CM Martinez-Amezaga Maitena M Traficante Carla I CI Giordano Rocío A RA Cornier Patricia G PG Mata Ernesto G EG Delpiccolo Carina Ml CM Boggián Dora B DB Giúdice Antonela Del AD Mainetti Leandro E LE Scharovsky Olga G OG Rozados Viviana R VR Rico María J MJ

Future science OA 20200123 3

<h4>Aim</h4>According to the need for the development of new anticancer agents, we have synthetized novel bioactive compounds and aimed to determine their antitumor action.<h4>Materials & methods</h4>We describe <i>in vitro</i> studies evaluating the effect of 35 novel chemical compounds on two triple negative murine mammary adenocarcinoma tumors.<h4>Results & conclusion</h4>Three compounds were selected because of their high antitumor activity and their low toxicity to normal cells. Their effec ...[more]

PMID: 32140251

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Project description:BackgroundRanpirnase (Rap) is an amphibian ribonuclease with reported antitumor activity, minimal toxicity, and negligible immunogenicity in clinical studies, but the unfavorable pharmacokinetics and suboptimal efficacy hampered its further clinical development. To improve the potential of Rap-based therapeutics, we have used the DOCK-AND-LOCK™ (DNL™) method to construct a class of novel IgG-Rap immunoRNases. In the present study, a pair of these constructs, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, comprising four copies of Rap linked to the CH3 and CK termini of hRS7 (humanized anti-Trop-2), respectively, were evaluated as potential therapeutics for triple-negative breast cancer (TNBC).MethodsThe DNL-based immunoRNases, (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2, were characterized and tested for biological activities in vitro on a panel of breast cancer cell lines and in vivo in a MDA-MB-468 xenograft model.Results(Rap)2-E1-(Rap)2 was highly purified (>95%), exhibited specific cell binding and rapid internalization in MDA-MB-468, a Trop-2-expressing TNBC line, and displayed potent in vitro cytotoxicity (EC50???1 nM) against diverse breast cancer cell lines with moderate to high expression of Trop-2, including MDA-MB-468, BT-20, HCC1806, SKBR-3, and MCF-7. In comparison, structural counterparts of (Rap)2-E1-(Rap)2, generated by substituting hRS7 with selective non-Trop-2-binding antibodies, such as epratuzumab (anti-CD22), were at least 50-fold less potent than (Rap)2-E1-(Rap)2 in MDA-MB-468 and BT-20 cells, both lacking the expression of the cognate antigen. Moreover, (Rap)2-E1-(Rap)2 was less effective (EC50 > 50 nM) in MDA-MB-231 (low Trop-2) or HCC1395 (no Trop-2), and did not show any toxicity to human peripheral blood mononuclear cells. In a mouse TNBC model, a significant survival benefit was achieved with (Rap)2-E1*-(Rap)2 when given the maximal tolerated dose.ConclusionsA new class of immunoRNases was generated with enhanced potency for targeted therapy of cancer. The promising results from (Rap)2-E1-(Rap)2 and (Rap)2-E1*-(Rap)2 support their further investigation as a potential treatment option for TNBC and other Trop-2-expressing cancers.

Dataset Information

Antitumor activity of new chemical compounds in triple negative mammary adenocarcinoma models.

Publications

Antitumor activity of new chemical compounds in triple negative mammary adenocarcinoma models.

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