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Anticancer Research 2007CKD-602, a topoisomerase I inhibitor, has antitumor activity in a broad spectrum of tumor types. STEALTH liposomal CKD-602 (S-CKD602) prolongs circulation of CKD-602 in...
BACKGROUND
CKD-602, a topoisomerase I inhibitor, has antitumor activity in a broad spectrum of tumor types. STEALTH liposomal CKD-602 (S-CKD602) prolongs circulation of CKD-602 in plasma, increases drug exposure in tumors and improves efficacy compared with free drug.
MATERIALS AND METHODS
Different dosing regimens of S-CKD602, free CKD-602 and topotecan were compared for antitumor activity in female athymic nude mice bearing human A375 melanoma, ES-2 ovarian, H82 SCLC or HT-29 colon tumor xenografts.
RESULTS
S-CKD602 was more efficacious than free drug in all tumor types studied. The therapeutic index (TI) of S-CKD602 was estimated to be approximately 6-fold greater than that of free CKD-602 in ES-2 and approximately 3-fold greater in H82 tumors. TI of S-CKD602 was approximately 2-fold greater than that of free CKD-602 and approximately 5-fold greater than that of topotecan in A375, and > or = 3-fold greater in HT-29 tumors. In A375 tumors, once-weekly dosing of S-CKD602 was superior to once every 2 weeks or twice weekly schedules.
CONCLUSION
The therapeutic index of S-CKD602 was greater than that of free CKD-602 and topotecan in several human tumor types.
Topics: Animals; Antineoplastic Agents, Phytogenic; Camptothecin; Carcinoma, Small Cell; Drug Administration Schedule; Enzyme Inhibitors; Female; HT29 Cells; Humans; Liposomes; Lung Neoplasms; Melanoma; Mice; Mice, Nude; Neoplasms; Topoisomerase II Inhibitors; Topotecan; Xenograft Model Antitumor Assays
PubMed: 17695551
DOI: No ID Found -
Molecules (Basel, Switzerland) Feb 2023The antitumor drug topotecan (TPT) is a potent inhibitor of topoisomerase I, triggering DNA breaks lethal for proliferating cancer cells. The mechanism is common to...
The antitumor drug topotecan (TPT) is a potent inhibitor of topoisomerase I, triggering DNA breaks lethal for proliferating cancer cells. The mechanism is common to camptothecins SN38 (the active metabolite of irinotecan) and belotecan (BLT). Recently, TPT was shown to bind the ribosomal protein L15, inducing an antitumor immune activation independent of topoisomerase I. We have modeled the interaction of four camptothecins with RPL15 derived from the 80S human ribosome. Two potential drug-binding sites were identified at Ile135 and Phe129. SN38 can form robust RPL15 complexes at both sites, whereas BLT essentially gave stable complexes with site Ile135. The empirical energy of interaction (ΔE) for SN38 binding to RPL15 is similar to that determined for TPT binding to the topoisomerase I-DNA complex. Molecular models with the ribosomal protein L11 sensitive to topoisomerase inhibitors show that SN38 can form a robust complex at a single site (Cys25), much more stable than those with TPT and BLT. The main camptothecin structural elements implicated in the ribosomal protein interaction are the lactone moiety, the aromatic system and the 10-hydroxyl group. The study provides guidance to the design of modulators of ribosomal proteins L11 and L15, both considered anticancer targets.
Topics: Humans; DNA Topoisomerases, Type I; Molecular Docking Simulation; Camptothecin; Antineoplastic Agents; Ribosomal Proteins; Topotecan; DNA; Topoisomerase I Inhibitors
PubMed: 36838813
DOI: 10.3390/molecules28041828 -
Acta Medica Okayama 2012The choice of chemotherapeutic drugs to treat patients with epithelial ovarian cancer has not depended on individual patient characteristics. We have investigated the...
The choice of chemotherapeutic drugs to treat patients with epithelial ovarian cancer has not depended on individual patient characteristics. We have investigated the correlation between in vitro chemosensitivity, as determined by the histoculture drug response assay (HDRA), and clinical responses in epithelial ovarian cancer. Fresh tissue samples were obtained from 79 patients with epithelial ovarian cancer. The sensitivity of these samples to 11 chemotherapeutic agents was tested using the HDRA method according to established methods, and we analyzed the results retrospectively. HDRA showed that they were more chemosensitive to carboplatin, topotecan and belotecan, with inhibition rates of 49.2%, 44.7%, and 39.7%, respectively, than to cisplatin, the traditional drug of choice in epithelial ovarian cancer. Among the 37 patients with FIGO stage III/IV serous adenocarcinoma who were receiving carboplatin combined with paclitaxel, those with carboplatin-sensitive samples on HDRA had a significantly longer median disease-free interval than patients with carboplatin-resistant samples (23.2 vs. 13.8 months, p < 0.05), but median overall survival did not differ significantly (60.4 vs. 37.3 months, p = 0.621). In conclusion, this study indicates that HDRA could provide useful information for designing individual treatment strategies in patients with epithelial ovarian cancer.
Topics: Adult; Aged; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Drug Screening Assays, Antitumor; Female; Humans; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms
PubMed: 22729108
DOI: 10.18926/AMO/48567 -
Molecular Medicine (Cambridge, Mass.) May 2019Cervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced...
BACKGROUND
Cervical cancer is the third most common gynecological malignancy. Conventional treatment options are known to be ineffective for the majority of patients with advanced or recurrent cervical cancer. Therefore, novel therapeutic agents for cervical cancer are necessary. In this study, the effects of CKD-602 in cervical cancer were investigated.
METHODS
Three established human, immortalized, cervical cancer cell lines (CaSki, HeLa and SiHa) were used in this study. Following treatment with CKD-602, apoptosis was quantified using fluorescein isothiocyanate Annexin V-FITC and propidium iodide (PI) detection kit and cell cycle analysis was analyzed using fluorescence activated cell sorting (FACS). Transwell chambers were used for invasion assays. Western blot assay was performed to analyze proteomics. CaSki cells were subcutaneously injected into BALB/c-nude mice and cervical cancer xenograft model was established to elucidate the antitumor effect of CKD-602 in vivo.
RESULTS
Treatment with CKD-602 induced apoptosis and increased expression of the enzyme PARP, cleaved PARP, and BAX. In addition, expression of phosphorylated p53 increased. Cell cycle arrest at G2/M phase and inhibition of invasion were detected after treatment with CKD-602. A significant decrease in cervical cancer tumor volume was observed in this in vivo model, following treatment with CKD-602.
CONCLUSIONS
This is the first report of CKD-602 having an antitumor effect in cervical cancer in both an in vitro and in vivo models. The results of this study indicate that CKD-602 may be a novel potential drug, targeting cervical cancer, providing new opportunities in the development of new therapeutic strategies.
Topics: Animals; Apoptosis; Camptothecin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Movement; Female; Flow Cytometry; G2 Phase Cell Cycle Checkpoints; HeLa Cells; Humans; Mice, Inbred BALB C; Mice, Nude; Topoisomerase I Inhibitors; Uterine Cervical Neoplasms; Xenograft Model Antitumor Assays
PubMed: 31138113
DOI: 10.1186/s10020-019-0089-y -
Clinical Cancer Research : An Official... Feb 2009S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in...
PURPOSE
S-CKD602 is a pegylated liposomal formulation of CKD602, a semisynthetic camptothecin analogue. Pegylated (STEALTH) liposomes can achieve extended drug exposure in plasma and tumor. Based on promising preclinical data, the first phase I study of S-CKD602 was done in patients with refractory solid tumors.
EXPERIMENTAL DESIGN
S-CKD602 was administered i.v. every 3 weeks. Modified Fibonacci escalation was used (three to six patients/cohort), and dose levels ranged from 0.1 to 2.5 mg/m2. Serial plasma samples were obtained over 2 weeks and total (lactone+hydroxyl acid) concentrations of encapsulated, released, and sum total (encapsulated+released) CKD602 measured by liquid chromatography-tandem mass spectrometry.
RESULTS
Forty-five patients (21 males) were treated. Median age, 62 years (range, 33-79 years) and Eastern Cooperative Oncology Group status, 0 to 1 (43 patients) and 2 (2 patients). Dose-limiting toxicities of grade 3 mucositis occurred in one of six patients at 0.3 mg/m2, grade 3 and 4 bone marrow suppression in two of three patients at 2.5 mg/m2, and grade 3 febrile neutropenia and anemia in one of six patients at 2.1 mg/m2. The maximum tolerated dose was 2.1 mg/m2. Partial responses occurred in two patients with refractory ovarian cancer (1.7 and 2.1 mg/m2). High interpatient variability occurred in the pharmacokinetic disposition of encapsulated and released CKD602.
CONCLUSIONS
S-CKD602 represents a promising new liposomal camptothecin analogue with manageable toxicity and promising antitumor activity. Phase II studies of S-CKD602 at 2.1 mg/m2 i.v. once every 3 weeks are planned. Prolonged plasma exposure over 1 to 2 weeks is consistent with STEALTH liposomes and provides extended exposure compared with single doses of nonliposomal camptothecins.
Topics: Adult; Aged; Camptothecin; Dose-Response Relationship, Drug; Female; Humans; Liposomes; Male; Middle Aged; Neoplasms; Polyethylene Glycols
PubMed: 19190127
DOI: 10.1158/1078-0432.CCR-08-1405 -
The Tohoku Journal of Experimental... Dec 2009Uterine cervical cancer is a leading cause of cancer-related death in the female population worldwide. In vitro chemosensitivity test is important to find effective...
Uterine cervical cancer is a leading cause of cancer-related death in the female population worldwide. In vitro chemosensitivity test is important to find effective drugs in uterine cervical cancer that requires the established chemotherapeutic strategies. The purpose of this study is to investigate the chemosensitivity of uterine cervical cancer using the histoculture drug response assay (HDRA). Sixty-five fresh tumor tissues were obtained from patients with cervical cancer: 47 squamous cell carcinomas, 11 adenocarcinomas, and 7 adenosquamous cell carcinomas. The median age was 44 years (range, 25-74 years), and the median follow-up duration was 26.3 months (range, 1.6-52.7 months). The clinical stage by the International Federation of Gynecologists and Obstetricians (FIGO) was stage I of 80.0% (52/65) and stage IIA of 13.8% (9/65). The inhibition rates of ten chemotherapeutic agents against these cancer tissues were tested using the HDRA method according to established methods. Five agents were evaluated as sensitive drugs in cervical cancer with inhibition rates of greater than 30%: 41.0% for carboplatin, 35.0% for cisplatin, 33.8% for paclitaxel, 41.4% for belotecan, and 49.2% for topotecan. Especially, carboplatin combined with paclitaxel showed an inhibition rate of 54.0%, which was higher than any other single agent. However, there were no noticeable differences in chemosensitivity according to histopathologic types and FIGO stage. Despite such limitation, the HDRA may be a promising chemosensitivity test to predict an effective drug for each patient. The HDRA could provide useful information that is invaluable for the design of individualized treatments in patients with cervical cancer.
Topics: Adult; Aged; Antineoplastic Agents; Cell Culture Techniques; Drug Screening Assays, Antitumor; Female; Humans; Middle Aged; Recurrence; Treatment Outcome; Uterine Cervical Neoplasms
PubMed: 19966525
DOI: 10.1620/tjem.219.277 -
International Journal of Nanomedicine 2012S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional...
S-CKD602 is a PEGylated liposomal formulation of CKD-602, a potent topoisomerase I inhibitor. The objective of this study was to characterize the bidirectional pharmacokinetic-pharmacodynamic (PK-PD) interaction between S-CKD602 and monocytes. Plasma concentrations of encapsulated CKD-602 and monocytes counts from 45 patients with solid tumors were collected following intravenous administration of S-CKD602 in the phase I study. The PK-PD models were developed and fit simultaneously to the PK-PD data, using NONMEM(®). The monocytopenia after administration of S-CKD602 was described by direct toxicity to monocytes in a mechanism-based model, and by direct toxicity to progenitor cells in bone marrow in a myelosuppression-based model. The nonlinear PK disposition of S-CKD602 was described by linear degradation and irreversible binding to monocytes in the mechanism-based model, and Michaelis-Menten kinetics in the myelosuppression-based model. The mechanism-based PK-PD model characterized the nonlinear PK disposition, and the bidirectional PK-PD interaction between S-CKD602 and monocytes.
Topics: Antineoplastic Agents; Camptothecin; Computer Simulation; Humans; Injections, Intravenous; Liposomes; Metabolic Clearance Rate; Models, Biological; Monocytes; Neoplasms; Polyethylene Glycols; Tissue Distribution; Topoisomerase I Inhibitors
PubMed: 23112576
DOI: 10.2147/IJN.S35751 -
Oncology Letters Jan 2015CKD-602 (7-[2-(N-isopropylamino) ethyl]-(20S)-camptothecin, belotecan) is a synthetic water-soluble camptothecin derivative and topoisomerase I inhibitor that has been...
CKD-602 (7-[2-(N-isopropylamino) ethyl]-(20S)-camptothecin, belotecan) is a synthetic water-soluble camptothecin derivative and topoisomerase I inhibitor that has been shown to exert a clinical anticancer effect on various types of tumor. In the present study, the anticancer effects of CKD-602 on the following three human oral squamous cell carcinoma (OSCC) cell lines originating from Korean cancer patients: YD-8 (tongue), YD-9 (buccal mucosa) and YD-38 (lower gingiva) were analyzed. The apoptotic proportion of the cells and cell cycle position were analyzed using flow cytometry. The expression of cell cycle regulatory proteins was detected by western blot analysis. CKD-602 was demonstrated to exert a time- and dose-dependent antiproliferative effect in all cell lines , however, susceptibility to CKD-602 at 72 h following treatment varied among the three cell lines, with 50% inhibition of cell viability at concentrations of 2.4 μg/ml for YD-8, 0.18 μg/ml for YD-9 and 0.05 μg/ml for YD-38. To investigate the underlying mechanism of the CKD-602 antiproliferative effect, a cell cycle-analysis was conducted in the three OSCC cell lines and CKD-602 treatment was observed to induce G2/M phase arrest. Furthermore, western blot analysis revealed that the expression levels of phospho-cdc2 (Tyr 15), cyclin A2 and cyclin B1 were increased in a time-dependent manner, following the administration of CKD-602. In the fluorescence-activated cell sorting analysis, the number of apoptotic cells was also increased in a dose-dependent manner following CKD-602 treatment of the OSCC cell lines. The results suggest that CKD-602 may inhibit the proliferation of OSCC oral cancer cells derived from samples from Korean patients by apoptosis and by G2/M phase arrest.
PubMed: 25435947
DOI: 10.3892/ol.2014.2648