Mechanisms underlying dose-limiting toxicities of conventional chemotherapeutic agents.

ABSTRACT

Dose-limiting toxicities (DLTs) are severe adverse effects that define the maximum tolerated dose of a cancer drug. In addition to the specific mechanisms of each drug, common contributing factors include inflammation, apoptosis, ion imbalances, and tissue-specific enzyme deficiencies. Among various DLTs are bleomycin-induced pulmonary fibrosis, doxorubicin-induced cardiomyopathy, cisplatin-induced nephrotoxicity, methotrexate-induced hepatotoxicity, vincristine-induced neurotoxicity, paclitaxel-induced peripheral neuropathy, and irinotecan, which elicits severe diarrhea. Currently, specific treatments beyond dose reduction are lacking for most toxicities. Further research on cellular and molecular pathways is imperative to improve their management. This review synthesizes preclinical and clinical data on the pharmacological mechanisms underlying DLTs and explores possible treatment approaches. A comprehensive perspective reveals knowledge gaps and emphasizes the need for future studies to develop more targeted strategies for mitigating these dose-dependent adverse effects. This could allow the safer administration of fully efficacious doses to maximize patient survival.

The dose-limiting toxicity of most anticancer drugs occurs via the activation of inflammatory/apoptosis/ROS pathways.Regarding the dose-limiting toxicity of most anticancer drugs, there is no specific treatment other than discontinuation or dose reduction.Accurately identifying the molecular pathways involved in the dose-limiting toxicity of anticancer drugs can help to identify new treatments.