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Pharmacological Research Oct 2019Twenty-five years ago, the cytotoxic drug irinotecan (IRT) was first approved in Japan for the treatment of cancer. For more than two decades, the IRT prodrug has... (Review)
Review
Twenty-five years ago, the cytotoxic drug irinotecan (IRT) was first approved in Japan for the treatment of cancer. For more than two decades, the IRT prodrug has largely contributed to the treatment of solid tumors worldwide. Nowadays, this camptothecin derivative targeting topoisomerase 1 remains largely used in combination regimen, like FOLFIRI and FOLFIRINOX, to treat metastatic or advanced solid tumors, such as colon, gastric and pancreatic cancers and others. This review highlights recent discoveries in the field of IRT and its derivatives, including analogues of the active metabolite SN38 (such as FL118), the recently approved liposomal form Nal-IRI and SN38-based immuno-conjugates currently in development (such as sacituzumab govitecan). New information about the IRT mechanism of action are presented, including the discovery of a new protein target, the single-stranded DNA-binding protein FUBP1. Significant progress has been made also to better understand and manage the main limiting toxicities of IRT, chiefly neutropenia and diarrhea. The role of drug-induced inflammation and dysbiosis is underlined and strategies to limit the intestinal toxicity of IRT are discussed (use of β-glucuronidase inhibitors, plant extracts, probiotics). The detailed knowledge of the metabolism of IRT has enabled the identification of potential biomarkers to guide patient selection and to limit drug-induced toxicities, but no robust IRT-specific therapeutic biomarker has been approved yet. IRT is a versatile chemotherapeutic agent which combines well with a variety of anticancer drugs. It offers a large range of drug combinations with cytotoxic agents, targeted products and immuno-active biotherapeutics, to treat a variety of advanced solid carcinoma, sarcoma and cancers with progressive central nervous system diseases. A quarter of century after its first launch, IRT remains an essential anticancer drug, largely prescribed, useful to many patients and scientifically inspiring.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Humans; Irinotecan; Neoplasms
PubMed: 31415916
DOI: 10.1016/j.phrs.2019.104398 -
Frontiers in Oncology 2022The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel...
PURPOSE
The aim of this study was to improve the intratumoral accumulation of an antibody-drug conjugate (ADC) and minimize its off-target toxicity, SKB264, a novel anti-trophoblast antigen 2 (TROP2) ADC that was developed using 2-methylsulfonyl pyrimidine as the linker to conjugate its payload (KL610023), a belotecan-derivative topoisomerase I inhibitor. The preclinical pharmacologic profiles of SKB264 were assessed in this study.
METHODS
The and pharmacologic profiles of SKB264, including efficacy, pharmacokinetics-pharmacodynamics (PK-PD), safety, and tissue distribution, were investigated using TROP2-positive cell lines, cell-derived xenograft (CDX), patient-derived xenograft (PDX) models, and cynomolgus monkeys. Moreover, some profiles were compared with IMMU-132.
RESULTS
, SKB264 and SKB264 monoclonal antibody (mAb) had similar internalization abilities and binding affinities to TROP2. After cellular internalization, KL610023 was released and inhibited tumor cell survival. , SKB264 significantly inhibited tumor growth in a dose-dependent manner in both CDX and PDX models. After SKB264 administration, the serum or plasma concentration/exposure of SKB264 (conjugated ADC, number of payload units ≥1), total antibody (Tab, unconjugated and conjugated mAb regardless of the number of the payload units), and KL610023 in cynomolgus monkeys increased proportionally with increasing dosage from 1 to 10 mg/kg. The linker stability of SKB264 was significantly enhanced as shown by prolonged payload half-life (SKB264 . IMMU-132, 56.3 h . 15.5 h). At the same dose, SKB264's exposure in tumor tissue was 4.6-fold higher than that of IMMU-132.
CONCLUSIONS
Compared with IMMU-132, the longer half-life of SKB264 had a stronger targeting effect and better antitumor activity, suggesting the better therapeutic potential of SKB264 for treating TROP2-positive tumors.
PubMed: 36620535
DOI: 10.3389/fonc.2022.951589 -
Archives of Pharmacal Research Nov 2007The purpose of this study was to investigate the effect of probenecid, an inhibitor of the MRP2/ ABCC transporter, on the pharmacokinetics and transport of belotecan...
The purpose of this study was to investigate the effect of probenecid, an inhibitor of the MRP2/ ABCC transporter, on the pharmacokinetics and transport of belotecan (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin). The effect of probenecid on the pharmacokinetics of belotecan was studied in rats. When belotecan was injected as a bolus dose of 5 mg/kg after probenecid was infused at a rate of 42.8 mg/2 mL/h/kg, the cumulative biliary excretion amounts and biliary clearance (CL(b)) of belotecan decreased (28.29 +/- 2.83 versus 19.96 +/- 1.45% of dose and 161.01 +/- 26.95 versus 92.66 +/- 1.45 mL/min/kg), whereas the systemic pharmacokinetics did not change. This indicates that the MRP2 transporter is involved in the biliary excretion of belotecan. The involvement of MRP2 in the secretory transport was further characterized using Caco-2 cell monolayers expressing MRP2. The apparent permeability across Caco-2 cell monolayers from basolateral to apical was 2.3 times greater than that from the apical to the basolateral side at the 50 microM belotecan. In addition, probenecid significantly decreased the basolateral-to-apical transport of belotecan (52.9%). These results indicate that MRP2 is involved in the secretory transport of belotecan in biliary excretion.
Topics: Animals; Bile; Biological Transport; Caco-2 Cells; Camptothecin; Humans; Male; Membrane Transport Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Probenecid; Rats
PubMed: 18087819
DOI: 10.1007/BF02977375 -
International Journal of Molecular... Jan 2021Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy...
Epithelial ovarian cancer remains the leading cause of mortality among all gynecologic malignancies owing to recurrence and ultimate development of chemotherapy resistance in the majority of patients. In the chemotherapy-resistant ovarian cancer preclinical model, we investigated whether AZD6738 (an ataxia telangiectasia and Rad3-related (ATR) inhibitor) could synergize with belotecan (a camptothecin analog and topoisomerase I inhibitor). In vitro, both chemotherapy-resistant and chemotherapy-sensitive ovarian cancer cell lines showed synergistic anti-proliferative activity with a combination treatment of belotecan and AZD6738. The combination also demonstrated synergistic tumor inhibition in mice with a chemotherapy-resistant cell line xenograft. Mechanistically, belotecan, a DNA-damaging agent, increased phospho-ATR (pATR) and phospho-Chk1 (pChk1) in consecutive order, indicating the activation of the DNA repair system. This consequently induced G2/M arrest in the cell cycle analysis. However, when AZD6738 was added to belotecan, pATR and pChk1 induced by belotecan alone were suppressed again. A cell cycle analysis in betotecan showed a sub-G1 increase as well as a G2/M decrease, representing the release of G2/M arrest and the induction of apoptosis. In ascites-derived primary cancer cells from both chemotherapy-sensitive and -resistant ovarian cancer patients, this combination was also synergistic, providing further support for our hypothesis. The combined administration of ATR inhibitor and belotecan proved to be synergistic in our preclinical model. This combination warrants further investigation in a clinical trial, with a particular aim of overcoming chemotherapy resistance in ovarian cancer.
Topics: Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Ataxia Telangiectasia Mutated Proteins; Camptothecin; Carcinoma, Ovarian Epithelial; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Checkpoint Kinase 1; Drug Synergism; Female; G2 Phase Cell Cycle Checkpoints; Humans; Immunohistochemistry; Indoles; Mice; Mice, Inbred BALB C; Mice, Nude; Morpholines; Ovarian Neoplasms; Phosphorylation; Pyrimidines; Sulfonamides; Sulfoxides; Xenograft Model Antitumor Assays
PubMed: 33513721
DOI: 10.3390/ijms22031223 -
British Journal of Cancer Feb 2021This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC). (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This study compared the efficacy/safety of the camptothecin analogues belotecan and topotecan for sensitive-relapsed small-cell lung cancer (SCLC).
METHODS
One-hundred-and-sixty-four patients were randomised (1:1) to receive five consecutive daily intravenous infusions of topotecan (1.5 mg/m) or belotecan (0.5 mg/m), every 3 weeks, for six cycles. Main outcomes were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), tolerability and toxicity. The study statistical plan was non-inferiority design with ORR as the endpoint.
RESULTS
In the belotecan vs. topotecan groups, ORR (primary endpoint) was 33% vs. 21% (p = 0.09) and DCR was 85% vs. 70% (p = 0.030). PFS was not different between groups. Median OS was significantly longer with belotecan than with topotecan (13.2 vs. 8.2 months, HR = 0.69, 95% CI: 0.48-0.99), particularly in patients aged <65 years, with more advanced disease (i.e., extensive-stage disease, time to relapse: 3-6 months), or Eastern Cooperative Oncology Group performance status 1 or 2. More belotecan recipients completed all treatment cycles (53% vs. 35%; p = 0.022).
CONCLUSIONS
The efficacy/safety of belotecan warrants further evaluation in Phase 3 trials. Belotecan potentially offers an alternative to topotecan for sensitive-relapsed SCLC, particularly in patients aged <65 years, with more advanced disease, or poor performance.
Topics: Aged; Camptothecin; Female; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Small Cell Lung Carcinoma; Topoisomerase I Inhibitors; Topotecan
PubMed: 33191408
DOI: 10.1038/s41416-020-01055-5 -
British Journal of Cancer Jan 2021This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
This Phase 2b study compared the efficacy and toxicity of belotecan and topotecan in recurrent ovarian cancer.
METHODS
Patients with platinum-sensitive recurrent or platinum-resistant recurrent ovarian cancer (PRROC) were randomised 1:1 to receive belotecan 0.5 mg/m or topotecan 1.5 mg/m for five consecutive days every 3 weeks. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS
A total of 140 (belotecan, n = 71; topotecan, n = 69) and 130 patients (belotecan, n = 66; topotecan, n = 64) were included in the intention-to-treat (ITT) and per-protocol (PP) populations. ORR did not differ significantly between the belotecan and topotecan groups (ITT, 29.6% versus 26.1%; PP, 30.3% versus 25%). Although PFS did not differ between the groups, belotecan was associated with improved OS compared with topotecan in the PP population (39.7 versus 26.6 months; P = 0.034). In particular, belotecan showed longer OS in PRROC and non-high-grade serous carcinoma (non-HGSC; PP, adjusted hazard ratios, 0.499 and 0.187; 95% confidence intervals 0.255-0.977 and 0.039-0.895). Furthermore, there were no differences in toxicities between the two groups.
CONCLUSIONS
Belotecan was not inferior to topotecan in terms of overall response for recurrent ovarian cancer.
CLINICAL TRIAL REGISTRATION
NCT01630018.
Topics: Adult; Aged; Antineoplastic Agents; Camptothecin; Carcinoma, Ovarian Epithelial; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Progression-Free Survival; Topotecan
PubMed: 32994466
DOI: 10.1038/s41416-020-01098-8 -
Cancer Research and Treatment 2006We wanted to demonstrate the anti-cancer effect and interaction between belotecan and cisplatin on gastric cancer cell line and we evaluated the mechanisms of this...
PURPOSE
We wanted to demonstrate the anti-cancer effect and interaction between belotecan and cisplatin on gastric cancer cell line and we evaluated the mechanisms of this synergistic effect in vitro.
MATERIALS AND METHODS
The growth inhibitory effect of belotocan and cisplatin against several gastric cancer cell lines (SNU-5, SNU-16 and SNU-601) was estimated by tetrazolium dye assay. The effect of a combination treatment was evaluated by the isobologram method. The biochemical mechanisms for the interaction between the drugs were analyzed by measuring the formation of DNA interstrand cross-links (ICLs) and DNA topo-I activity.
RESULTS
Belotecan showed synergism with cisplatin for growth inhibitory effect on the gastric cancer cell lines SNU-5, and SNU-16, but this was subadditive on the SNU-601 cell line. The formation of DNA ICLs in SNU-16 cells by cisplatin was increased by combination with belotecan, but this was not affected in SNU-601 cells. The topo-I inhibition by belotecan was enhanced at high concentrations of cisplatin in SNU-16, but not in SNU-601 cells.
CONCLUSION
Belotecan and cisplatin show various combination effect against gastric cancer cells. The synergism between cisplatin and belotecan could be the result of one of the following mechanisms: the modulating effect of belotecan on the repair of cisplatin-induced DNA adducts and the enhancing effect of cisplatin on the belotecan-induced topo-I inhibitory effect.
PubMed: 19771277
DOI: 10.4143/crt.2006.38.3.159 -
Medicinal Research Reviews Jul 2015Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the... (Review)
Review
Camptothecins (CPTs) are cytotoxic natural alkaloids that specifically target DNA topoisomerase I. Research on CPTs has undergone a significant evolution from the initial discovery of CPT in the late 1960s through the study of synthetic small-molecule derivatives to investigation of macromolecular constructs and formulations. Over the past years, intensive medicinal chemistry efforts have generated numerous CPT derivatives. Three derivatives, topotecan, irinotecan, and belotecan, are currently prescribed as anticancer drugs, and several related compounds are now in clinical trials. Interest in other biological effects, besides anticancer activity, of CPTs is also growing exponentially, as indicated by the large number of publications on the subject during the last decades. Therefore, the main focus of the present review is to provide an ample but condensed overview on various biological activities of CPT derivatives, in addition to continued up-to-date coverage of anticancer effects.
Topics: Anti-Infective Agents; Antineoplastic Agents; Camptothecin; Humans
PubMed: 25808858
DOI: 10.1002/med.21342 -
Annals of Oncology : Official Journal... Jan 2008Belotecan (Camtobell, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a new camptothecin analogue. This study aimed to investigate the safety and efficacy of single-agent...
BACKGROUND
Belotecan (Camtobell, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a new camptothecin analogue. This study aimed to investigate the safety and efficacy of single-agent belotecan for small-cell lung cancer (SCLC).
PATIENTS AND METHODS
Twenty-seven patients with chemotherapy-naive or chemosensitive SCLC were treated with belotecan 0.5 mg/m(2)/day on days 1-5 of a 3-week cycle. All 27 patients were assessable for toxicity, and 21 patients assessable for response.
RESULTS
Nine patients (42.9%) showed objective tumor responses including one complete response; seven (63.6%) in 11 chemotherapy-naive patients; and two (20.0%) in 10 chemosensitive patients. With a median follow-up of 5 years, median progression-free and survival time for chemotherapy-naive patients were 4.8 months and 11.9 months, respectively, while the corresponding values for chemosensitive patients were 3.3 months and 10.5 months, respectively. The most common toxicity was neutropenia.
CONCLUSION
Belotecan was active in SCLC patients as a single agent, warranting further investigations of belotecan in combination with platinum or other active agents.
Topics: Aged; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Carcinoma, Small Cell; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Neutropenia; Salvage Therapy; Topoisomerase I Inhibitors; Treatment Outcome
PubMed: 17823384
DOI: 10.1093/annonc/mdm437 -
International Journal of Cancer Aug 2013The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the...
The prognosis of patients diagnosed with glioblastoma remains dismal in spite of the current concomitant chemoradiotherapy with temozolomide. In particular, the resistance to temozolomide appears to be the greatest obstacle to the treatment of glioblastoma. In the present study, we evaluated in vitro and in vivo the antitumor effects of combination therapy of cilengitide with belotecan, a camptothecin derivate, to treat experimental glioblastoma. The therapeutic effects of the drugs on the U87MG and U251MG human glioblastoma cell lines were assessed using in vitro cell viability and apoptosis assays. The combination treatment group with cilengitide and belotecan enhanced the cytotoxic effects to the glioblastoma cell lines and increased the apoptosis of the tumor cells compared to monotherapy with either drug alone in vitro. Nude mice with established U87MG glioblastoma were assigned to the following four groups: control, cilengitide, belotecan and combination treatment. The volume of tumors and length of survival were also measured. Animals in the combination therapy group demonstrated a significant reduction of tumor volume and an increase in survival (p < 0.05). Immunohistochemistry revealed a decrease in angiogenesis by cilengitide and an increase in apoptosis by cilengitide and belotecan in vivo. The combination therapy of cilengitide with belotecan presented more cytotoxic effects compared to the monotherapy of either drug in vitro and in vivo. This combination protocol may serve as an alternative treatment option for glioblastoma.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Brain Neoplasms; Camptothecin; Cell Line, Tumor; Cell Proliferation; Cell Survival; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Snake Venoms; Topoisomerase I Inhibitors; Xenograft Model Antitumor Assays
PubMed: 23354807
DOI: 10.1002/ijc.28058