Camptothein-Based Anti-Cancer Therapies and Strategies to Improve Their Therapeutic Index

Camptothecin and its derivatives (CPTs) are potent antineoplastic agents that exert their effects by inhibiting DNA topoisomerase I, leading to apoptosis during cell proliferation. Since their discovery in the 1960s, CPTs have faced challenges such as low water solubility, pH-dependent lactone ring instability, and severe off-target toxicities. Despite extensive research, only two CPTs, irinotecan and topotecan, have received health authority approval. Ongoing clinical trials continue to explore the use of CPTs in combination with targeted therapies and immunotherapies to expand their clinical use. Drug delivery systems, including liposomes and antibody–drug conjugates (ADCs), have significantly enhanced the therapeutic index of CPTs. Liposomal irinotecan (Onivyde®, Ipsen, Paris, France) and two ADCs delivering CPT payloads, trastuzumab deruxtecan (Enhertu®, Daiichi Sankyo, Tokyo, Japan) and sacituzumab govitecan (Trodelvy®, Gilead Sciences, Inc., Foster City, CA, USA), have demonstrated substantial efficacy and safety. There is promise that novel strategies such as inverse targeting and co-dosing with anti-idiotypic distribution enhancers may expand the utility of CPT ADCs. This review highlights CPT therapies in clinical use and discusses approaches to further enhance their therapeutic selectivity.