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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 -
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 -
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 -
Journal of Thoracic Oncology : Official... Apr 2012Belotecan (Camtobell, CKD602) is a new camptothecin-derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this study was to evaluate the...
INTRODUCTION
Belotecan (Camtobell, CKD602) is a new camptothecin-derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this study was to evaluate the efficacy and safety of belotecan monotherapy as a second-line therapy in patients with relapsed or refractory small cell lung cancer (SCLC).
METHODS
Between June 2008 and August 2011, a total of 50 patients with relapsed or refractory SCLC were treated with belotecan 0.5 mg/m for 5 consecutive days, every 3 weeks. We evaluated the overall response rate (ORR), the progression-free survival (PFS), and the overall survival (OS), and toxicity according to sensitivity to initial chemotherapy.
RESULTS
The median age was 66 years (range, 43-84 years) and Eastern Cooperative Oncology Group performance was 0 or 1 in 34 patients (68%) and 2 in 16 patients (32%). Twenty patients (40%) had sensitive relapse and 30 patients (60%) had refractory disease. The ORR, PFS, and OS for sensitive patients were 20% (95% confidence interval [CI], 8-40), 2.8 months (95% CI, 0.53-5.06), and 6.5 months (95% CI, 1.58-11.42), respectively. In the refractory group, the ORR, PFS, and OS were 10% (95% CI, 1-21), 1.5 months (95% CI, 1.25-1.75), and 4.0 months (95% CI, 3.40-4.60), respectively. Most commonly reported grade-3 or -4 adverse events included neutropenia (54%), thrombocytopenia (38%), and anemia (32%).
CONCLUSION
Belotecan showed modest activity with an acceptable safety profile as a second-line therapy in patients with relapsed or refractory SCLC.
Topics: Adult; Aged; Aged, 80 and over; Camptothecin; Carcinoma, Small Cell; Disease-Free Survival; Female; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Topoisomerase I Inhibitors
PubMed: 22425922
DOI: 10.1097/JTO.0b013e31824b23cb -
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 -
Journal of Thoracic Disease Oct 2020Systemic treatment in small cell lung carcinoma has been a challenge for oncologists for decades. The high propensity for recurrence is usually due to distant... (Review)
Review
Systemic treatment in small cell lung carcinoma has been a challenge for oncologists for decades. The high propensity for recurrence is usually due to distant metastasis, which makes systemic treatment an essential component of treatment in small cell lung carcinoma. The regimen of cisplatin and etoposide (established in the mid-1980's) concurrently with thoracic radiotherapy followed by prophylactic cranial irradiation (PCI) remains the standard of care in limited stage disease. Despite numerous trials, this regimen has not been improved upon. The standard combination regimen of cisplatin and etoposide has been compared to alternative platinum-containing regimens with drugs like epirubicin, irinotecan, paclitaxel, topotecan, pemetrexed, amrubicin and belotecan. Non-platinum containing regimens like ifosfamide and etoposide have also been tested. Attempts to intensify therapy have included the addition of a third drug like paclitaxel, ifosfamide, tirapazamine, tamoxifen, and thalidomide. Maintenance therapy following induction with chemotherapy, vandetanib and interferon-alpha have also been attempted. Molecularly directed targeted therapies and immunotherapeutic agents are areas of active research. In this review, we discuss the various systemic therapy options in limited stage small cell lung carcinoma, from the historical regimens to the modern-day therapy and promising areas of research. We also discuss the role of growth factors, the optimal number of chemotherapy cycles, the use of prognostic and predictive factors, the optimal timing of chemotherapy and the treatment of special populations of patients including older patients, and patients with comorbidities.
PubMed: 33209466
DOI: 10.21037/jtd-2019-sclc-11 -
Methods and Findings in Experimental... Dec 2010Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Thomson Reuters Integrity(SM), the drug discovery and development portal, http://www.thomsonreutersintegrity.com. This issue focuses on the following selection of drugs: 17-Hydroxyprogesterone caproate; Abacavir sulfate/lamivudine, Aclidinium bromide, Adalimumab, Adefovir, Alemtuzumab, Alkaline phosphatase, Amlodipine, Apilimod mesylate, Aripiprazole, Axitinib, Azacitidine; Belotecan hydrochloride, Berberine iodide, Bevacizumab, Bortezomib, Bosentan, Bryostatin 1; Calcipotriol/hydrocortisone, Carglumic acid, Certolizumab pegol, Cetuximab, Cinacalcet hydrochloride, Cixutumumab, Coumarin, Custirsen sodium; Darbepoetin alfa, Darifenacin hydrobromide, Darunavir, Dasatinib, Denibulin hydrochloride, Denosumab, Diacetylmorphine, Dulanermin, Duloxetine hydrochloride; Ecogramostim, Enfuvirtide, Entecavir, Enzastaurin hydrochloride, Eplerenone, Escitalopram oxalate, Esomeprazole sodium, Etravirine, Everolimus, Ezetimibe; Fenofibrate/pravastatin sodium, Ferric carboxymaltose, Flavangenol, Fondaparinux sodium; Glutamine, GSK-1024850A; Hepatitis B hyperimmunoglobulin, Hib-MenC, HIV-LIPO-5; Immunoglobulin intravenous (human), Indacaterol maleate, Indibulin, Indium 111 (¹¹¹In) ibritumomab tiuxetan, Influenza A (H1N1) 2009 Monovalent vaccine, Inhalable human insulin, Insulin glulisine; Lapatinib ditosylate, Leucovorin/UFT; Maraviroc, Mecasermin, MMR-V, Morphine hydrochloride, Morphine sulfate/naltrexone hydrochloride, Mycophenolic acid sodium salt; Naproxen/esomeprazole magnesium, Natalizumab; Oncolytic HSV; Paliperidone, PAN-811, Paroxetine, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b/ribavirin, Pegvisomant, Pemetrexed disodium, Pimecrolimus, Posaconazole, Pregabalin; Raltegravir potassium, Ranelic acid distrontium salt, Rasburicase, Rilpivirine hydrochloride; Sertindole, Sivelestat sodium hydrate, Sorafenib, Sumatriptan succinate/naproxen sodium, Sunitinib malate; Tafluprost, Telithromycin, Temsirolimus, Tenofovir disoproxil fumavate, Tenofovir disoproxil fumarate/emtricitabine, Teriparatide, Ticagrelor, Tigecycline, Tipranavir, Tirapazamine, Trimetrexate; Ulipristal acetate; Valganciclovir hydrochloride, Vicriviroc, Vorinostat; Yttrium 90 (90Y) ibritumomab tiuxetan.
Topics: Clinical Trials as Topic; Humans
PubMed: 21225012
DOI: 10.1358/mf.2010.32.10.1573763 -
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 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 -
Canadian Respiratory Journal 2016. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC). This study compared the toxicities and efficacies of... (Comparative Study)
Comparative Study
. Topotecan and belotecan are camptothecin derivatives that are used to treat small cell lung cancer (SCLC). This study compared the toxicities and efficacies of belotecan and topotecan monotherapies in patients with SCLC. . We retrospectively reviewed data from 94 patients with SCLC (with or without prior chemotherapy) who were treated using belotecan monotherapy ( = 59, 188 cycles) or topotecan monotherapy ( = 35, 65 cycles) between September 2003 and December 2011. . Thrombocytopenia occurred during 42% and 61.5% of the belotecan and topotecan cycles, respectively ( = 0.007). Significant differences between belotecan and topotecan were also observed for grade 4/5 lung infection (3.2% versus 10.8%, resp.; = 0.003), all-grade headache (3.2% versus 10.8%, resp.; = 0.017), and grade 4/5 increased liver enzymes (0.5% versus 4.6%, resp.; = 0.023). The median TTPDs, CSSs, and OSs were 14 months and 11.6 months ( = 0.646), 10 months and 7 months ( = 0.179), and 34.5 months and 21.4 months ( = 0.914) after belotecan and topotecan monotherapy, respectively. . Belotecan monotherapy may be safer than topotecan monotherapy in SCLC patients. And in terms of efficacy, belotecan could be comparable to topotecan monotherapy.
Topics: Adult; Age Factors; Aged; Aged, 80 and over; Camptothecin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Republic of Korea; Retrospective Studies; Small Cell Lung Carcinoma; Survival Analysis; Topoisomerase I Inhibitors; Topotecan
PubMed: 28018128
DOI: 10.1155/2016/3576201