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Asian Pacific Journal of Cancer... Nov 2016Objective: Gimatecan is a new camptothecin (CPT) analogue that inhibits tumor growth by targeting DNA topoisomerase I (TOP I) and introducing strong and persistent DNA...
Objective: Gimatecan is a new camptothecin (CPT) analogue that inhibits tumor growth by targeting DNA topoisomerase I (TOP I) and introducing strong and persistent DNA cleavage. Anti-tumor activity has been demonstrated with a wide range of solid tumors in previous preclinical and clinical studies. Here, we investigated for the first time the effects of gimatecan on the proliferation of hepatocellular carcinoma (HCC) cells both in vitro and in vivo. Methods: Anticancer efficacy of gimatecan were evaluated in a panel of HCC cell lines and corresponding mouse xenograft models. Inhibition of cell proliferation was measured by CellTiter-Glo cell viability assay. In vivo, gimatecan and control preparations were orally administered every four days, for a total of four times. Tumor volume and body weights of the mice were measured twice weekly. Results: In vitro cytotoxicity evaluation showed that gimatecan inhibited the proliferation of a large panel of HCC cell lines in a dose dependent manner, with IC50 values ranging between 12.1~1085.0 nM. In vivo evaluation in mouse xenograft models showed significant antitumor effects of gimatecan at 0.8mg/kg and 0.4mg/kg as compared to the control group. Conclusion: This study suggested that gimatecan may have the potential to be used as a chemotherapeutic agent for the treatment of HCC.
PubMed: 28030910
DOI: 10.22034/APJCP.2016.17.11.4853 -
Journal of Translational Medicine Dec 2017We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines...
BACKGROUND
We investigated antitumor activity and underlying mechanisms of DNA topoisomerase I (TopI) inhibitor gimatecan and irinotecan in gastric cancer (GC) in vitro cell lines and in vivo patient-derived xenograft (PDX) models.
METHODS
GC cell lines SNU-1, HGC27, MGC803 and NCI-N87 were used to evaluate cell viability and apoptosis after gimatecan or irinotecan treatment, using a cell proliferation assay and flow cytometry, respectively. DNA TopI expression and critical molecules of PI3K/AKT, MAPK and apoptosis signaling pathways were analyzed with western blot. For in vivo studies, five PDXs models were treated with gimatecan or irinotecan to assess its antitumor activity. Immunohistochemistry staining of Ki-67 was performed after mice were sacrificed.
RESULTS
Gimatecan inhibited the proliferation of GC cells in vitro in a dose- and time-dependent manner by inducing apoptosis, and gimatecan had greater inhibitory effects than irinotecan. In addition, both gimatecan and irinotecan demonstrated significant tumor growth inhibition in in vivo PDX models. Gimatecan treatment significantly inhibited the expression of DNA TopI, phosphorylated AKT (pAKT), phosphorylated MEK (pMEK) and phosphorylated ERK (pERK). Meanwhile, gimatecan could also activate the JNK2 and p38 MAPK pathway as indicated by upregulation of phosphorylated p38 MAPK (p-p38) and phosphorylated JNK2 (pJNK2).
CONCLUSIONS
For the first time, we have shown that the antitumor activity of gimatecan in GC via suppressing AKT and ERK pathway and activating JNK2 and p38 MAPK pathway, which indicated that gimatecan might be an alternative to irinotecan in the treatment of GC.
Topics: Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Cell Line, Tumor; Cell Proliferation; Female; Humans; Ki-67 Antigen; MAP Kinase Signaling System; Mice, Inbred NOD; Mice, SCID; Proto-Oncogene Proteins c-akt; Stomach Neoplasms; Time Factors; Xenograft Model Antitumor Assays
PubMed: 29237470
DOI: 10.1186/s12967-017-1360-z -
Cell Death & Disease May 2018Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the...
Esophageal squamous cell carcinoma (ESCC) is a frequently diagnosed and deadly malignancy with few standard therapeutic options. Camptothecins are considered one of the most promising antitumor drugs. A modified lipophilic analog, gimatecan, was synthesized as a novel oral camptothecin and showed impressive effects in various tumors, but its therapeutic efficacy and mechanisms in ESCC remain unclear. This study investigated the antitumor efficacy and mechanisms of gimatecan in ECSS both in vitro and in vivo. Using ESCC cell lines, cell line-derived xenografts and patient-derived xenografts models, we evaluated gimatecan's inhibition of tumor growth, and compared its antitumor efficacy with that of irinotecan. Topoisomerase I function and expression were assessed using the DNA relaxation assay and Western blotting, respectively. DNA damage was evaluated by Western blotting. Cell cycle progression and cell apoptosis were assessed using flow cytometry and Western blotting. Gimatecan could significantly suppress tumor growth in vivo and inhibit tumor cell proliferation in vitro, which was superior to irinotecan. Gimatecan suppressed the function and expression of topoisomerase I. It also caused DNA damage and activated the phosphorylation of multiple checkpoint gatekeepers, such as ATM, ATR, BRCA1, H2AX, CHK1, CHK2, and p53. It induced S phase arrest, enhanced the expression of p21, and suppressed the expression of CDK2 and cyclin A. Induction of apoptosis was accompanied by increases in Bax, cleaved-caspase 3 activation, cleaved-caspase 9 induction, and a decrease in Bcl-2. The molecular and phenotypic changes induced by gimatecan were stronger than that of irinotecan. In ESCC, gimatecan suppressed the expression and function of topoisomerase I, induced DNA damage and intra-S phase cell cycle arrest, and resulted in apoptosis. And the results suggest that gimatecan has higher potency in inhibiting ESCC tumor growth than irinotecan, providing a rational novel therapeutic strategy for future clinical evaluation.
Topics: Antineoplastic Agents; Apoptosis; Camptothecin; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; DNA Damage; DNA Topoisomerases, Type I; Esophageal Squamous Cell Carcinoma; Humans; Irinotecan
PubMed: 29855512
DOI: 10.1038/s41419-018-0700-0 -
Biochemical Pharmacology May 2013The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan...
The aim of this work is the in vitro and ex vivo assessment of the leishmanicidal activity of camptothecin and three analogues used in cancer therapy: topotecan (Hycantim®), gimatecan (ST1481) and the pro-drug irinotecan (Camptosar®) as well as its active metabolite SN-38 against Leishmania infantum. The activity of camptothecin and its derivatives was studied on extracellular L. infantum infrared-emitting promastigotes and on an ex vivo murine model of infected splenocytes with L. infantum fluorescent amastigotes. In situ formation of SDS/KCl precipitable DNA-protein complexes in Leishmania promastigotes indicated that these drugs are DNA topoisomerase IB poisons. The inhibitory potency of camptothecin derivatives on recombinant L. infantum topoisomerase IB was assessed in vitro showing that gimatecan is the most active compound preventing the relaxation of supercoiled DNA at submicromolar concentrations. Cleavage equilibrium assays in Leishmania topoisomerase IB show that gimatecan changes the equilibrium towards cleavage at much lower concentrations than the other camptothecin derivatives and that this effect persists over time. Gimatecan and camptothecin were the most powerful compounds preventing cell growth of free-living L. infantum promastigotes within the same concentration range. All these compounds killed L. infantum splenocyte-infecting amastigotes within the nanomolar range. The amastigote form showed higher sensitivity to topoisomerase IB poisons (with high therapeutic selectivity indexes) than free-living promastigotes. All the compounds assayed poisoned L. infantum DNA topoisomerase IB leading to a strong leishmanicidal effect. Camptothecin derivatives are suitable for reducing the parasitic burden of ex vivo infected splenocytes. The selectivity index of gimatecan makes it a promising drug against this neglected disease.
Topics: Animals; Antineoplastic Agents; Camptothecin; Cells, Cultured; DNA Topoisomerases, Type I; Genes, Reporter; Inhibitory Concentration 50; Irinotecan; Kinetics; Leishmania infantum; Life Cycle Stages; Luminescent Proteins; Mice; Prodrugs; Protozoan Proteins; Spleen; Topoisomerase I Inhibitors; Trypanocidal Agents; Red Fluorescent Protein
PubMed: 23466420
DOI: 10.1016/j.bcp.2013.02.024 -
Cancers Dec 2022Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer... (Review)
Review
Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of other plant-derived bioactive compounds are in the clinical development phase against cancer, such as gimatecan, elomotecan, etc. Additionally, the conjugation of natural compounds with anti-cancerous drugs, or some polymeric carriers particularly targeted to epitopes on the site of interest to tumors, can generate effective targeted treatment therapies. Cognizance from such pharmaceutical research studies would yield alternative drug development strategies through natural sources which could be economical, more reliable, and safe to use.
PubMed: 36551687
DOI: 10.3390/cancers14246203 -
Neoplasia (New York, N.Y.) Feb 2005To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a...
To investigate the cellular/molecular basis of the activity of a novel lipophilic camptothecin, gimatecan (ST1481), against slowly proliferating cells, we performed a comparative study of topotecan and gimatecan in human bladder cancer models (HT1376 and MCR). Gimatecan was significantly more effective than topotecan in inhibiting the growth of HT1376 tumor, thus reflecting antiproliferative potency. In both HT1376 and MCR cells, gimatecan caused a persistent S-phase arrest, indicating an efficient DNA damage checkpoint. This response was consistent with a cytostatic effect, because no evidence of apoptosis was detected. In contrast to gimatecan, topotecan at equitoxic concentrations caused an early and persistent downregulation of topoisomerase I. Modulation of protein level could not be solely ascribed to the proteasome-mediated degradation of the enzyme because the proteasome inhibitor PS341 sensitized MCR but not HT1376 cells to camptothecins, suggesting alternative mechanisms of drug-induced topoisomerase I downregulation. Indeed, the two camptothecins caused a differential inhibition of topoisomerase I transcription, which is more marked in topotecan-treated cells. The HT1376 model was more sensitive to this immediate decrease of mRNA level. Our data document a marked antitumor activity of gimatecan against a bladder carcinoma model. A limited downregulation of topoisomerase I by gimatecan provides additional insights into the cellular basis of drug potency.
Topics: Animals; Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Camptothecin; DNA Topoisomerases, Type I; Disease Models, Animal; Down-Regulation; Female; Humans; Mice; Mice, Nude; Protease Inhibitors; Pyrazines; RNA, Messenger; S Phase; Topoisomerase I Inhibitors; Topotecan; Transplantation, Heterologous; Tumor Cells, Cultured; Urinary Bladder Neoplasms
PubMed: 15802020
DOI: 10.1593/neo.04397 -
Annals of Oncology : Official Journal... Mar 2007Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and...
BACKGROUND
Gimatecan is an orally bioavailable camptothecin analogue with preclinical findings of promising antitumor activity. A phase I design of concerted dose escalation and dosing duration was implemented to assess the potential schedule dependency of tolerability that emerged from animal studies.
PATIENTS AND METHODS
Gimatecan was given daily for five consecutive days per week for 1, 2 or 3 weeks every 28 days. Plasma levels of total gimatecan were measured on the first and the last day of treatment in each schedule.
RESULTS
Overall, 108 patients were treated with 0.8-7.2 mg/m(2) of gimatecan per cycle. The main toxicity was myelosuppression with dose-limiting thrombocytopenia. In the 1-, 2- and 3-week schedule, the maximum tolerated doses were 4.5, 5.6 and 6.4 mg/m(2). Diarrhea and asthenia were of low grade and of minor clinical relevance, while the higher incidence of nausea and vomiting in the 1-week schedule required the use of antiemetic prophylaxis. Due to the prolonged half-life (approximately 77 h), the plasma concentration of gimatecan increased from the first to the last day of dosing. Six partial responses were observed.
CONCLUSIONS
Tolerability of gimatecan was schedule dependent. Further testing with schedules taking into account its long persistence in human plasma is worthwhile.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Phytogenic; Camptothecin; Dose-Response Relationship, Drug; Drug Administration Schedule; Europe; Female; Half-Life; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome
PubMed: 17150998
DOI: 10.1093/annonc/mdl418 -
Annals of Oncology : Official Journal... Apr 2010A prospective phase II study was conducted to evaluate the efficacy and toxicity of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or...
BACKGROUND
A prospective phase II study was conducted to evaluate the efficacy and toxicity of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer.
PATIENTS AND METHODS
Patients had a maximum of three prior chemotherapy lines with no more than two prior platinum-containing regimens and a progression-free interval after the last dose of platinum <12 months. A total dose of 4 mg/m(2)/cycle (0.8 mg/m(2)/day from day 1 to day 5) was administered, repeated every 28 days.
RESULTS
From June 2005 to December 2005, 69 assessable patients were enrolled. The best overall response to study treatment by combined CA-125 and RECIST criteria was partial response in 17 patients (24.6%) and disease stabilization in 22 patients (31.9%). The median time to progression and overall survival were 3.8 and 16.2 months, respectively. A total of 312 cycles were administered. Neutropenia grade 4 and thrombocytopenia grade 4 occurred in 17.4% and 7.2% of patients, respectively. Diarrhea grade 4 was never observed. Asthenia and fatigue were reported by 36.2% and 18.8% of patients, but were all grade 2 or less.
CONCLUSION
Gimatecan is a new active agent in previously treated ovarian cancer with myelosuppression as main toxicity.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Chemotherapy, Adjuvant; Fallopian Tube Neoplasms; Female; Humans; Middle Aged; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Peritoneal Neoplasms; Platinum; Recurrence; Taxoids
PubMed: 19906760
DOI: 10.1093/annonc/mdp514 -
Frontiers in Cell and Developmental... 2023In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis,...
In 2023, approximately 288,300 new diagnoses of prostate cancer will occur, with 34,700 disease-related deaths. Death from prostate cancer is associated with metastasis, enabled by progression of tumor phenotypes and successful extracapsular extension to reach Batson's venous plexus, a specific route to the spine and brain. Using a mouse-human tumor xenograft model, we isolated an aggressive muscle invasive cell population of prostate cancer, called DU145 with a distinct biophysical phenotype, elevated histone H3K27, and increased matrix metalloproteinase 14 expression as compared to the non-aggressive parent cell population called DU145. Our goal was to determine the sensitivities to known chemotherapeutic agents of the aggressive cells as compared to the parent population. High-throughput screening was performed with 5,578 compounds, comprising of approved and investigational drugs for oncology. Eleven compounds were selected for additional testing, which revealed that vorinostat, 5-azacitidine, and fimepinostat (epigenetic inhibitors) showed 2.6-to-7.5-fold increases in lethality for the aggressive prostate cancer cell population as compared to the parent, as judged by the concentration of drug to inhibit 50% cell growth (IC). On the other hand, the DU145 cells were 2.2-to-4.0-fold resistant to mitoxantrone, daunorubicin, and gimatecan (topoisomerase inhibitors) as compared to DU145. No differences in sensitivities between cell populations were found for docetaxel or pirarubicin. The increased sensitivity of DU145 prostate cancer cells to chromatin modifying agents suggests a therapeutic vulnerability occurs after tumor cells invade into and through muscle. Future work will determine which epigenetic modifiers and what combinations will be most effective to eradicate early aggressive tumor populations.
PubMed: 38046670
DOI: 10.3389/fcell.2023.1285372 -
Frontiers in Microbiology 2021This study investigates susceptibility toward three fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), multiple fluoroquinolone-resistance mechanisms, and...
Overexpression of Efflux Pumps, Mutations in the Pumps' Regulators, Chromosomal Mutations, and AAC(6')-Ib-cr Are Associated With Fluoroquinolone Resistance in Diverse Sequence Types of Neonatal Septicaemic : A 7-Year Single Center Study.
This study investigates susceptibility toward three fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin), multiple fluoroquinolone-resistance mechanisms, and epidemiological relationship of neonatal septicaemic . Previous studies on fluoroquinolone resistance in focused primarily on ciprofloxacin susceptibility and assessed a particular mechanism of resistance; a more holistic approach was taken here. Epidemiological relationship was evaluated by Multi Locus Sequence Typing. Minimum Inhibitory Concentrations of fluoroquinolones was determined with and without efflux pump inhibitors. Overexpression of efflux pumps, resistance-nodulation-cell-division (RND)-type, and multidrug and toxic compound extrusion (MATE)-type efflux pumps were evaluated by reverse transcriptase-qPCR. Mutations within regulatory proteins (AdeRS, AdeN, and AdeL) of RND-pumps were examined. Chromosomal mutations, presence of and ' were investigated. were highly diverse as 24 sequence-types with seven novel STs (ST-1440/ST-1441/ST-1481/ST-1482/ST-1483/ST-1484/ST-1486) were identified among 47 High resistance to ciprofloxacin (96%), levofloxacin (92%), and particularly moxifloxacin (90%) was observed, with multiple mechanisms being active. Resistance to 4 generation fluoroquinolone (moxifloxacin) in neonatal isolates is worrisome. Mutations within GyrA (S83L) and ParC (S80L) were detected in more than 90% of fluoroquinolone-resistant (FQRAB) spread across 10 different clonal complexes (CC1/CC2/CC10/CC25/CC32/CC126/CC149/CC216/CC218/CC513). Efflux-based FQ resistance was found in 65% of FQRAB with ≥2 different active pumps in 38% of strains. Overexpression of was highest (2.2-34-folds) followed by , , and . Amino acid changes in the regulators (AdeRS/AdeN/AdeL) either as single or multiple substitutions substantiated the overexpression of the pumps. Diverse mutations within AdeRS were detected among different CCs whereas mutations within AdeN linked to CC10 and CC32. Chromosomal mutations and active efflux pumps were detected simultaneously among 64% of FQRAB. Presence of was also high (74% of FQRAB) but were absent. As most FQRABs had chromosomal mutations, this was considered predominant, however, isolates where pumps were also active had higher MIC values, establishing the critical role of the efflux pumps. The high variability of FQ susceptibility among FQRAB, possessing the same set of mutations in , , and efflux pump regulators, was also noted. This reveals the complexity of interpreting the interplay of multiple resistance mechanisms in .
PubMed: 33776950
DOI: 10.3389/fmicb.2021.602724