GMDTC Chelating Agent Attenuates Cisplatin-Induced Systemic Toxicity without Affecting Antitumor Efficacy

Area of Science:

• Pharmacology
• Toxicology
• Oncology

Background:

• Cisplatin is a vital platinum-based chemotherapy drug for various cancers.
• Severe toxicities (nephrotoxicity, ototoxicity) and resistance limit cisplatin efficacy.
• Metal chelators show potential in mitigating platinum drug-associated problems.

Purpose of the Study:

• To evaluate the protective effects of a new chelating agent, GMDTC, against cisplatin-induced toxicities.
• To assess GMDTC's impact on cisplatin's anti-tumor activity.

Main Methods:

• In vitro studies using HK2 cells to assess cytotoxicity and apoptosis.
• In vivo studies in a 4T1 breast cancer mouse model.
• Evaluation of kidney function (BUN, creatinine), renal histology, auditory function, hematology, and hepatology.
• Assessment of tumor growth, size, and metastasis.

Main Results:

• GMDTC reduced cisplatin-induced apoptosis and cytotoxicity in HK2 cells.
• GMDTC mitigated cisplatin-induced nephrotoxicity, ototoxicity, hematotoxicity, and hepatotoxicity in mice.
• GMDTC did not compromise cisplatin's anti-tumor efficacy.
• Reduced intracellular platinum accumulation and deposition in kidneys were observed with GMDTC.

Conclusions:

• GMDTC effectively reduces cisplatin-induced systemic toxicities.
• GMDTC acts as a chemotherapy protector by preventing platinum accumulation and aiding its removal.
• GMDTC shows potential as a rescue agent to overcome platinum drug toxicity and resistance without affecting therapeutic activity.