Avaliação da atividade citotóxica e antitumoral de novos derivados de quinazolina em modelo de adenocarcinoma mamário

Abstract

Breast cancer is an uncontrolled growth of epithelial cells originating from the mammary ducts or lobules. The National Cancer Institute estimates that breast cancer is the most common cancer in women, with 73,610 new cases of breast cancer registered each year for the three-year period 2023-2025, corresponding to a rate of 41.89 cases per 100,000 women. Unfortunately, many traditional therapies for breast cancer treatment have limitations that diminish their effectiveness, including problems related to adverse reactions and the development of drug resistance. Quinazoline derivatives have demonstrated efficacy against various types of cancer, including drug-resistant forms, thus representing a rich source for the development of new chemotherapeutic agents for the treatment of breast cancer. This study evaluated the cytotoxic potential of new quinazolines through in vitro cytotoxicity assays and in vivo efficacy studies. An in vitro screening revealed that two new quinazolines, named KDY3 and KDY23, showed promising activity in several breast cancer cell lines (4T1, MDA-MB-231, MCF-7), exhibiting IC50 values in the range of 5.72 to 14.74 μM. Therefore, both substances were selected for in vivo studies. The substances were tested in a syngeneic breast cancer model induced by orthotopic inoculation of murine 4T1 breast cancer cells into BALB/c mice. The mice were divided into control and treated groups. In the treatment groups, animals were treated with KDY3 (15 or 30 mg/kg/week, with an initial dose of 100 or 200 mg/kg), and KDY23 (15 or 30 mg/kg every three days, with an initial dose of 100 or 200 mg/kg) or doxorubicin (5 mg/kg/week) as a standard control. In the 30 mg/kg/week dosing regimen with an initial dose of 200 mg/kg, KDY3 significantly reduced tumor volume (338.61 ± 97.53 mm³ vs. 545.49 ± 151.56 mm³ in untreated control groups; p = 0.024) without lethal effects and without significant reduction in animal weight. Animals in the doxorubicin group, however, experienced significant weight reduction. This may suggest that experimental treatment with KDY3 may have demonstrated lower toxicity compared to the control treatment with doxorubicin. Cytokine dosage assays revealed that KDY3, at a dosage regimen of 30 mg/kg/week with an initial dose of 200 mg/kg, showed an immunomodulatory effect, as it increased the level of IFN-γ in intratumoral tissue. In conclusion, the quinazoline KDY3 can be considered a promising drug candidate for the treatment of breast cancer. KDY23, on the other hand, showed good results in vitro, but dosage adjustments are needed to reduce its toxicity.