Irinotecan-Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview

Abstract

Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan's molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells' resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.

Keywords: SN-38; drug combinations; drug resistance; irinotecan; new formulations; topoisomerases.

Figure 1

Mechanisms of action for human topoisomerases. (A) Topoisomerase IA binds to DNA at a particular binding site, and then claves one strand, forming a transient 5′-phosphotyrosyl bond. The other DNA strand is transferred through the resultant break, allowing DNA to relax. Religation ends the process. (B) Toposiomerase IB works in a controlled rotation mechanism and in contrast to type IA enzymes forms a 3′-phosphotyrosyl bond with a DNA molecule. Both type I (A&B) topoisomerases do not require ATP hydrolysis as a source of energy. (C) Topoisomerase II binds to both ends of the DNA molecule, forms a double-strand break, and passes a segment of dsDNA through. This reaction is ATP-dependent [19].

Figure 2

Chemical structures of camptothecin and irinotecan.

Figure 3

The ternary irinotecan–topoisomerase I–nicked DNA complex. Inhibition of topoisomerase I (blue) bound to the DNA molecule (yellow) with CPT-11 (red).

Figure 4

Mechanisms of cell death induced by irinotecan. The ternary irinotecan–topoisomerase I–nicked DNA complex with topoisomerase I (Topo I) inhibitor (SN-38) disables religation of the nicked strand and prevents topoisomerase release. Collision of the formed complex with advancing replication forks results in the formation of double-strand breaks (DSBs). This is followed by DNA damage response (DDR) signaling and TP53-induced gene expression of pro-apoptotic genes such as apoptosis regulator (BAX), phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), or p53 up-regulated modulator of apoptosis (PUMA). Furthermore, down-regulation of the Bcl-2-like protein 1 isoform protein (BCL-xL) protein allows BAX and Bcl-2 homologous antagonist (BAK) embedding into the mitochondrial membrane and the formation of pores that allow the release of cytochrome C (cytC) from mitochondria and the subsequent formation of apoptosome with apoptotic protease-activating factor 1 (APAF-1) protein and procaspase-9. The activation of procaspase to caspase 9 (Casp-9) results in proteolytic cleavage and the conversion of procaspase 3 into active caspase 3 (Casp-3), which executes apoptosis [37,38,44,49,51].

Figure 5

Overview of irinotecan metabolism. CPT-11 is a prodrug that is converted to active metabolite ethyl-10-hydroxy-camptothecin (SN-38) by liver carboxylesterase converting enzymes (CES1/2) and is then transported to the liver by 1B1 polypeptide (OATP1B1) and inactivated by microsomal uridine 5′-diphospho-glucuronosyltransferase enzymes (UGTs): UGT1A1 and UGT1A9. Irinotecan is transported to bile by a group of the ATP-binding cassette transporters (ABC transporters): ABCB1, ABCC1, ABCC2, and ABCG2. Irinotecan is efficiently metabolized by cytochrome P450 enzymes: CYP3A4 and CYP3A5. This results in the generation of less active metabolites APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino] carbonyloxycamptothecin) and NPC (7-ethyl-10-[4-amino-1-piperidino] carbonyloxycamptothecin). NPC (but not APC) can be further converted to SN-38 by CES1, and CES2 gut microbiota may also participate in irinotecan metabolism by the production of β-glucuronidase, which catalyzes the breakdown of SN-38G to SN-38. The inhibition of topoisomerase I (TOP1) results in DNA damage, replication fork arrest, and apoptotic cell death [53,54,55,56,57,58,59,60,61,62].