Preclinical Evaluation of the Methyl (Z)-2-(isothioureidomethyl)-2-pentenoateHydrobromide: Antitumor Efficacy and Safety Profile in a Murine Melanoma Model

INTRODUCTION: Melanoma is a malignancy often resistant to conventional therapies, highlighting the need for novel agents that effectively target tumor progression and subdue apoptotic resistance. Isothiouronium salts have shown promising anticancer potential; however, their in vivo potential remains largely unexplored. This study aimed to evaluate the preclinical safety and antitumor efficacy of the isothiouronium derivative ISMF08. METHODS: C57BL/6J mice underwent acute and repeated-dose toxicity studies to determine the maximum tolerated dose (MTD) of IS-MF08. Following MTD determination, melanoma-bearing mice inoculated with B16F10 cells were treated intraperitoneally with IS-MF08 for 10 days. Tumor growth, survival, body weight, hematological parameters, and histopathology of liver, kidneys, and tumor tissue were evaluated. RESULTS: The MTD was defined as 15 mg/kg. Repeated dosing with IS-MF08 at 12 mg/kg was well tolerated and promoted tumor growth inhibition (87%) and increased survival. Treatment also attenuated weight loss and tumor- induced anemia and leukocytosis. Histological analyses of tumors showed reduced neoplastic cell density and signs of collagen deposition. Mild histological changes in the liver and kidneys were observed at higher doses, along with an isolated increase in ALT levels and a slight increase in serum creatinine. In contrast, other liver enzymes (AST, ALT), TB, DB, total protein, albumin, and renal function markers remained within physiological limits. DISCUSSION: Preclinical evidence suggests that IS-MF08 is a promising candidate for further development as a multitargeted antineoplastic compound. It has demonstrated selectivity, tumor growth inhibition, and a manageable toxicity profile, positioning it as a potential therapeutic option for melanoma and possibly other solid tumors with similar resistance mechanisms. However, several limitations should be acknowledged. The antitumor activity of ISMF08 was evaluated in a single syngeneic mouse model (B16F10), which may not fully recapitulate the heterogeneity of human tumors. Furthermore, the lack of pharmacokinetic data and long-term toxicity assessments limits conclusions about the compound's safety over prolonged periods. Additionally, histopathological and hematological analyses have provided initial insights into the drug's tolerability. Future studies should expand the range of tumor models, explore immunological interactions, and incorporate molecular assays and bioavailability profiles to better elucidate the therapeutic potential and translational applicability of IS-MF08. CONCLUSION: IS-MF08 demonstrated robust antitumor activity with a safety profile. Despite the limitations of the present study, these findings support its continued development as a potential multi-target chemotherapeutic agent. Further studies are necessary to elucidate the therapeutic potential and translational applicability of ISMF08.