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Kumar, S.; Sherman, M.Y. Irinotecan as an Anticancer Drug. Encyclopedia. Available online: https://encyclopedia.pub/entry/44901 (accessed on 18 November 2024).
Kumar S, Sherman MY. Irinotecan as an Anticancer Drug. Encyclopedia. Available at: https://encyclopedia.pub/entry/44901. Accessed November 18, 2024.
Kumar, Santosh, Michael Y. Sherman. "Irinotecan as an Anticancer Drug" Encyclopedia, https://encyclopedia.pub/entry/44901 (accessed November 18, 2024).
Kumar, S., & Sherman, M.Y. (2023, May 26). Irinotecan as an Anticancer Drug. In Encyclopedia. https://encyclopedia.pub/entry/44901
Kumar, Santosh and Michael Y. Sherman. "Irinotecan as an Anticancer Drug." Encyclopedia. Web. 26 May, 2023.
Irinotecan as an Anticancer Drug
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This entry is adapted from the peer-reviewed paper 10.3390/ijms24087233

Irinotecan (SN-38) is a potent and broad-spectrum anticancer drug that targets DNA topoisomerase I (Top1). It exerts its cytotoxic effects by binding to the Top1-DNA complex and preventing the re-ligation of the DNA strand, leading to the formation of lethal DNA breaks. Following the initial response to irinotecan, secondary resistance is acquired relatively rapidly, compromising its efficacy. There are several mechanisms contributing to the resistance, which affect the irinotecan metabolism or the target protein. 

irinotecan drug resistance topoisomerase I dose escalation

1. Introduction

Irinotecan (CPT-11) is a chemotherapeutic agent that causes cancer cell killing by poisoning topoisomerase I (Top1) in the cell. It is a semisynthetic analog of camptothecin, which was originally isolated from the Chinese/Tibetan ornamental tree Camptotheca acuminata [1][2][3]. Resistance model-based studies uncovered several mechanisms of cellular resistance to this agent and, accordingly, multiple approaches were tested in clinical trials to circumvent the resistance [4][5][6]. Beside primary resistance, the major clinical problem is development of secondary resistance in the course of the drug treatment, which is often observed with DNA-damaging chemotherapeutic drugs, such as irinotecan [7][8][9] or doxorubicin [6][10][11]. It is commonly understood that the development of drug resistance in cancer cells is defined by the change in expression or function of the target protein [8][12], changes in the ability of cells to undergo cell death [13][14][15], or changes in drug metabolism [16][17][18][19].
Importantly, both in experimental and clinical settings, secondary resistance usually develops gradually in the course of multiple exposures to the drug. It is unclear why changes in transcriptome [9][12][16][18][19][20][21], metabolism [12][22][23], or mutations in drug targets [7][12][24][25][26][27][28][29][30] do not appear abruptly but require multiple drug administrations [12][14][16][31][32]. This puzzling requirement suggests a distinct mode of resistance that may require a gradual accumulation of a large number of mutations or epigenetic events. Each of these events may have a minor effect on the drug response, but cumulatively they provide significant resistance.

2. Irinotecan’s Mode of Action

One of the classes of drugs that are frequently used in cancer therapy is inhibitors of DNA supercoil relaxing topoisomerases, including Top1 and Top2. Type I topoisomerases (Top1) cause relaxation of super helical DNA by generating a transient single-strand nick, followed by DNA relaxation and re-ligation. The enzyme subtypes perform very specialized functions, e.g., Class IA can only relax negative supercoiled DNA, whereas Class IB can introduce positive supercoils, relaxing and separating DNA molecules in daughter chromosomes after DNA replication. Top1 plays major role in transcription and replication and is highly active in pericentromeric and centromeric regions of the genome [33][34][35][36][37][38][39]. In contrast, type II topoisomerases (Top2) mediate ATP-dependent cleavage of both strands of the DNA double helix, followed by crossing of the DNA double-strand (ds) through the transiently opened gap [40]. Mammalian cells have two Top2 isoenzymes, Top2α and Top2β [35]. Top2α is associated with DNA replication and, as a consequence, cell proliferation, while Top2β may play a role in transcription [39][41].
Major Top1 or Top2 inhibitors function by stabilizing the transient complexes formed between these enzymes and DNA [37][42]. Stabilization of these otherwise fleeting “cleavable complexes” can lead to formation of double-strand breaks (DSBs) when the DNA replication forks collide with the topoisomerase-DNA complexes [37][42]. Similarly, the inhibitor-stabilized Top1 or Top2 “cleavable complexes” located on the transcribed template strand can also result in the formation of DSBs when RNA polymerase molecules collide with them within the transcribed DNA regions [40]. DSBs are recognized by the cell as lethal lesions and can trigger apoptosis [43][44]. These cytotoxic effects are responsible for the anti-cancer activity of topoisomerase inhibitors.
A most widely used Top1 inhibitor, irinotecan is a prodrug that, upon activation, generates an active compound, SN-38 [2][45][46][47][48]. Upon treatment of cancer cells, SN-38 binds to Top1 and stabilizes Top1-DNA complexes [2][49] (Figure 1). The SN-38 molecule stacks against the base pairs flanking the Top1-induced cleavage site and poisons the enzyme [2][49]. This conversion suppresses the 3′-OH free end and makes it unavailable for re-ligation. Inhibition of re-ligation of nicked DNA strands leads to single strand breaks, which have a high probability of conversion to highly toxic DSB. As the drug works not only during transcription [50], but also during replication, these DNA-Top1-SN38 covalent adjuncts could lead to replication fork stalling and the arrest of DNA replication.
Figure 1. The mechanism of DNA generation breaks upon irinotecan exposure. Normal function of Top1: ① supercoiled sensing and nick development by Top1 leads to ② relaxation, then ③ Top1 re-ligates the nicked backbone and leaves the site. In the case of irinotecan exposure, Top1 gets covalently crosslinked to DNA, then ④ ligation of 3′-OH free end is blocked, which could translate into ⑤ double strand break and facilitate cytotoxicity.
High-intensity transcription and replication enhances the supercoiling of DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC must manage this interfering torsional change. In a recent study, a direct association of MYC with Top1 and Top2 was demonstrated [51]. Beyond recruiting topoisomerases, MYC directly stimulated their activities. These MYC complexes with Top1 and Top2 increased their activities at promoters, coding regions, and enhancers [51]. Such enhancement of the activity of Top1 and its recruitment to DNA may create additional cleavage sites upon the drug treatment. In line with this suggestion, it was demonstrated that the overexpression of MYC enhances the sensitivity of colon cancer cells to the parental drug, camptothecin [51][52]. At the same time, MYC can activate the DNA damage response, which results in induction of the DSB repair system [51]. This in turn could reduce the response to irinotecan, since DSB repair plays a critical role in survival of cells treated with irinotecan.

3. Clinical Use of Irinotecan

In the USA, irinotecan has been approved for use against colorectal cancer in combination with 5-fluorouracil (5-FU) and leucovorin (FOLFIRI regimen). With therapy regimens like FOLFIRI, the median survival rate of a patient with metastatic colorectal cancer has improved from 8 months to 24 months [47]. Irinotecan is also used in combination with Capecitabine (pro-drug of 5-FU) (XELIRI regimen). Currently, both regimens are considered first-line therapy for cancer treatment. Several studies have been conducted to assess the effects of these combinations, and they have demonstrated that they are equally effective, with certain variations in median survival rates [1][53][54][55][56][57][58][59]. The usage of these schemes is defined by several factors such as geographical regions, patient genetics, individual response rate, oncologist’s preference, and socio-economic factors.
Another promising combination of irinotecan is with antibodies against EGFR, such as Cetuximab, for treatment of patients with wild-type K-Ras colorectal cancers and certain other cancer types, with 5-FU/leucovorin as a first-line treatment [60]. It is important to note that initial studies suggested that patients with colorectal tumors characterized by high microsatellite instability (MSI) might respond better to irinotecan-based chemotherapy [61][62]. However, subsequent data did not support a predictive value of MSI status in relation to treatment response [63][64].

4. Resistance development

There are several standard mechanisms of resistance to the drug.  Among which MDRs or mutations in the target are prevalent. In addition, there is a unique mechanism of rapid development of resistance associated with the accumulation of multiple mutations resulting from DSB repair of Top1-generated DNA breaks[65]. These mutations prevent interaction of Top1 with these specific sites upon following exposure to irinotecan and thus lead to resistance.

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