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Molecules (Basel, Switzerland) Oct 2021Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and...
Mosquito-borne viruses including dengue, Zika, and Chikungunya viruses, and parasites such as malaria and endanger health and economic security around the globe, and emerging mosquito-borne pathogens have pandemic potential. However, the rapid spread of insecticide resistance threatens our ability to control mosquito vectors. Larvae of were screened with the Medicines for Malaria Venture Pandemic Response Box, an open-source compound library, using INVAPP, an invertebrate automated phenotyping platform suited to high-throughput chemical screening of larval motility. We identified rubitecan (a synthetic derivative of camptothecin) as a hit compound that reduced larval motility. Both rubitecan and camptothecin displayed concentration dependent reduction in larval motility with estimated EC of 25.5 ± 5.0 µM and 22.3 ± 5.4 µM, respectively. We extended our investigation to adult mosquitoes and found that camptothecin increased lethality when delivered in a blood meal to adults at 100 µM and 10 µM, and completely blocked egg laying when fed at 100 µM. Camptothecin and its derivatives are inhibitors of topoisomerase I, have known activity against several agricultural pests, and are also approved for the treatment of several cancers. Crucially, they can inhibit Zika virus replication in human cells, so there is potential for dual targeting of both the vector and an important arbovirus that it carries.
Topics: Aedes; Animals; Antiviral Agents; Camptothecin; Drug Discovery; Female; High-Throughput Screening Assays; Humans; Insecticide Resistance; Insecticides; Larva; Mosquito Vectors; Motor Activity; Pandemics; Topoisomerase I Inhibitors; Vector Borne Diseases; Virus Replication; Zika Virus
PubMed: 34684807
DOI: 10.3390/molecules26206226 -
Annals of Oncology : Official Journal... Nov 2002Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate... (Clinical Trial)
Clinical Trial Comparative Study
BACKGROUND
Rubitecan (9-nitrocamptothecin, 9-NC, Orathecin) and gemcitabine have single-agent activity in pancreatic and ovarian carcinoma. We conducted a phase I trial to evaluate the maximum tolerated dose (MTD) and toxicities of this combination in advanced malignancies.
PATIENTS AND METHODS
Twenty-one patients with refractory or recurrent malignancies were enrolled in this dose escalation trial. Dose escalation proceeded from a starting level of rubitecan at 0.75 mg/m(2)/day administered orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) administered intravenously on days 1 and 8 of a 21-day cycle.
RESULTS
The MTD was defined as rubitecan 1 mg/m(2) administered orally days 1-5 and 8-12, and gemcitabine 1000 mg/m(2) administered intravenously over 30 min days 1 and 8, given every 21 days. Dose-limiting toxicity was myelosuppression including neutropenia and thrombocytopenia. Other side effects included diarrhea, nausea, vomiting and fatigue. Five patients with stable disease were observed among 18 evaluable patients.
CONCLUSIONS
The recommended phase II dose is rubitecan 1 mg/m(2) given orally on days 1-5 and 8-12 in combination with gemcitabine 1000 mg/m(2) as a 30-min intravenous infusion on days 1 and 8 of a 21-day cycle.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy, Needle; Camptothecin; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Infusions, Intravenous; Lymphatic Metastasis; Male; Maximum Tolerated Dose; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Neoplasms; Risk Assessment; Survival Analysis; Treatment Outcome; Gemcitabine
PubMed: 12419757
DOI: 10.1093/annonc/mdf342 -
Molecules (Basel, Switzerland) Feb 2014Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our...
Advanced small cell lung cancer (SCLC) has a dismal prognosis. Modulation of the camptothecin topotecan, approved for second-line therapy, may improve response. Our recent finding of synergistic enhancement of the cytotoxic activity of camptothecin (CPT) by cyclin-dependent kinase 4 inhibitors is extended here to a panel of camptothecin analogs comprising 10-hydroxy-CPT (HOCPT), topotecan (TPT; 9-[(dimethylamino)-methyl]-10-hydroxy-CPT), 9-amino-CPT (9AC), 9-nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin) and 10-hydroxy-9-nitrocamptothecin (CPT109) in combination with PD0332991, CDK4I, roscovitine and olomoucine. SCLC cell lines employed are chemoresistant NCI-H417 and DMS153 and the chemosensitive SCLC26A line established at our institution. The CPT analogs exhibiting highest cytotoxicity towards the three SCLC lines tested were SN38 and 9AC, followed by rubitecan, HOCPT, TPT and CPT109. NCI-H417 and DMS153 revealed an approximately 25-fold and 7-fold higher resistance compared to the chemosensitive SCLC26A cell line. Whereas the CDK4/6 inhibitor PD0332991 proved less effective to chemosensitize SCLC cells to CPT analogs, the CDK inhibitors CDK4I, roscovitine and olomoucine gave comparable chemosensitization effects in combination with 9AC, SN38, rubitecan and to a lesser extent with TPT and CPT109, not directly related with topoisomerase mRNA expression. In conclusion, small chemical modifications of the parent CPT structure result in differing cytotoxicities and chemomodulatory effects in combination with CDKIs of the resulting analogs.
Topics: Antineoplastic Agents; Camptothecin; Cell Line, Tumor; Cyclin-Dependent Kinases; Drug Synergism; Enzyme Inhibitors; Humans; Irinotecan; Small Cell Lung Carcinoma; Topotecan
PubMed: 24549232
DOI: 10.3390/molecules19022077 -
The Oncologist Mar 2005Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits.... (Clinical Trial)
Clinical Trial
BACKGROUND
Additional systemic treatments for locally advanced or metastatic pancreatic cancer are needed, as current treatment options produce only modest survival benefits. Rubitecan (Orathecin; Supergen Inc., Dublin, CA, http://www.supergen.com) is an orally active camptothecin derivative with demonstrated responses in patients with pancreatic cancer in early clinical trials. This phase II, open-label trial was developed to assess the safety and efficacy of rubitecan in patients with locally advanced or metastatic pancreatic cancer refractory to conventional chemotherapy.
METHODS
Fifty-eight patients with failed or relapsed advanced pancreatic cancer after receiving at least one prior chemotherapy regimen were enrolled to receive eight consecutive weeks of treatment with rubitecan at a dose of 1.5 mg/m2 orally on five consecutive days per week, followed by 2 days off therapy, repeatedly. The primary end point was response rate. Time to progression, overall survival, changes in CA19-9 levels, and the composite measure of clinical benefit response were evaluated as secondary end points.
RESULTS
Among 43 patients with measurable disease, 7% (3/43) achieved partial responses and 16% (7/43) had disease stabilization for an overall response and disease stabilization rate of 23%. All responses were confirmed by independent radiology review. Median survival was longer in responding patients than in the overall study cohort (10 months versus 3 months). Gastrointestinal and hematologic toxicities were the most commonly reported adverse events.
CONCLUSION
Oral rubitecan produced responses and was well tolerated by heavily pretreated patients with refractory pancreatic cancer. The overall risk-benefit profile of oral rubitecan appears promising, supporting further evaluation in phase III trials in patients with refractory and chemotherapy-naive pancreatic cancer.
Topics: Administration, Oral; Adult; Aged; Antineoplastic Agents; Camptothecin; Disease Progression; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Survival Analysis
PubMed: 15793221
DOI: 10.1634/theoncologist.10-3-183 -
Acta Pharmacologica Sinica Mar 2003To study the pharmacokinetics and the excretion of 9-nitro-20(S)-camptothecin (9-NC) in rats.
AIM
To study the pharmacokinetics and the excretion of 9-nitro-20(S)-camptothecin (9-NC) in rats.
METHODS
Each rat was given a single dose at random by iv or ig administration. Serial plasma and excreta samples were collected and the pharmacokinetic behavior of 9-NC in rats was characterized by specific liquid chromatographic assays. Individual 9-NC plasma-concentration data were analyzed by both noncompartmental and compartmental analysis. For dose proportionality, AUC- and Cmax-dose relationships were evaluated by linear regression, and t1/2 and CLtot were compared by an analysis of variance model. Also, the excretion of the parent drug was estimated.
RESULTS
After iv administration of 9-NC at the doses of 1.5, 3, and 6 mg/kg, the t1/2 values for 9-NC were estimated to be 0.5, 0.5, and 0.7 h, respectively, and the mean AUC0-t values were 633, 1606, and 3011 h.microg.L(-1), respectively. 9-NC was rapidly absorbed, reaching mean Cmax of 203, 417, and 1150 microg/L at Tmax of 0.3, 0.2, and 0.3 h at the doses of 3, 6, and 12 mg/kg, respectively. The mean AUC0-t values were 269, 439, and 881 h.microg.L(-1), and the mean t1/2 values were 1.7, 0.9, and 0.9 h, respectively. The absolute oral bioavailability of 9-NC was calculated to be 14.6 %, which was consistent with the ratio of the total cumulative excretion in the urine and bile by ig to that by iv injection.
CONCLUSION
The kinetic process of 9-NC in rats in vivo was best fitted to a two-compartmental model. For iv administration, the pharmacokinetics are not dose-dependent. The oral bioavailability of 9-NC was low. Renal excretion was the primary elimination route of the parent drug after iv administration, however, after ig administration the unchanged drug was largely excreted in the feces because of the poor absorption.
Topics: Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; Bile; Biological Availability; Camptothecin; Feces; Injections, Intravenous; Random Allocation; Rats; Rats, Wistar; Tissue Distribution; Urine
PubMed: 12617776
DOI: No ID Found -
Cancer Biology & Therapy Jul 2013Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by...
Chordoma is a rare, slow growing malignant tumor arising from remnants of the fetal notochord. Surgery is the first choice for chordoma treatment, followed by radiotherapy, although postoperative complications remain significant. Recurrence of the disease occurs frequently due to the anatomy of the tumor location and violation of the tumor margins at the initial surgery. Currently, there are no effective drugs available for patients with chordoma. Due to the rarity of the disease, there is limited opportunity to test agents in clinical trials and no concerted effort to develop agents for chordoma in the pharmaceutical industry. To rapidly and efficiently identify small molecules that inhibit chordoma cell growth, we screened the NCGC Pharmaceutical Collection (NPC) containing approximately 2800 clinically approved and investigational drugs at 15 different concentrations in chordoma cell lines, U-CH1 and U-CH2. We identified a group of drugs including bortezomib, 17-AAG, digitoxin, staurosporine, digoxin, rubitecan, and trimetrexate that inhibited chordoma cell growth, with potencies from 10 to 370 nM in U-CH1 cells, but less potently in U-CH2 cells. Most of these drugs also induced caspase 3/7 activity with a similar rank order as the cytotoxic effect on U-CH1 cells. Cantharidin, digoxin, digitoxin, staurosporine, and bortezomib showed similar inhibitory effect on cell lines and 3 primary chordoma cell cultures. The combination treatment of bortezomib with topoisomerase I and II inhibitors increased the therapeutic potency in U-CH2 and patient-derived primary cultures. Our results provide information useful for repurposing currently approved drugs for chordoma and potential approach of combination therapy.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Chordoma; Drug Screening Assays, Antitumor; Humans; Small Molecule Libraries
PubMed: 23792643
DOI: 10.4161/cbt.24596 -
Journal of Biomolecular Structure &... May 2021In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to...
In December 2019, COVID-19 epidemic was described in Wuhan, China, and the infection has spread widely affecting hundreds of thousands. Herein, an effort was made to identify commercially available drugs in order to repurpose them against coronavirus by the means of structure-based virtual screening. In addition, ZINC15 library was used to identify novel leads against main proteases. Human TMPRSS2 3D structure was first generated using homology modeling approach. Our molecular docking study showed four potential inhibitors against Mpro enzyme, two available drugs (Talampicillin and Lurasidone) and two novel drug-like compounds (ZINC000000702323 and ZINC000012481889). Moreover, four promising inhibitors were identified against TMPRSS2; Rubitecan and Loprazolam drugs, and compounds ZINC000015988935 and ZINC000103558522. ADMET profile showed that the hits from our study are safe and drug-like compounds. Furthermore, molecular dynamic (MD) simulation and binding free energy calculation using the MM-PBSA method was performed to calculate the interaction energy of the top-ranked drugs.Communicated by Ramaswamy H. Sarma.
Topics: COVID-19; Cysteine Endopeptidases; Drug Repositioning; Humans; Molecular Docking Simulation; Peptide Hydrolases; Pharmaceutical Preparations; Protease Inhibitors; SARS-CoV-2; Viral Nonstructural Proteins
PubMed: 32306862
DOI: 10.1080/07391102.2020.1758791 -
Acta Pharmacologica Sinica Feb 2003To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters.
AIM
To study the structure-activity relationship of alkyl 9-nitrocamptothecin esters.
METHODS
Two alkyl 9-nitrocamptothecin (9NC) esters 5g and 5h were prepared by esterification reactions of 9NC with valeric anhydride and heptanoic anhydride, respectively. Eight 9NC esters 5a-5h were tested for cytotoxicity against human leukemia cell lines HL-60 and U-937. Flow cytometry analysis was used to identify the cell cycle phase targeted by the esters and quantify the extent of ester-induced cell death (apoptosis).
RESULTS
Esters 5b and 5c demonstrated great abilities to inhibit growth of the leukemia cells followed by induction of apoptosis; esters 5a, 5e, and 5g induced slight perturbations in the cell cycle at high concentrations; and esters 5d, 5f, and 5h were completely inactive against the cell lines tested. Thus these esters showed the cell anti-proliferative activity in an order of 5b approximately 5c>5a approximately 5e approximately 5g>5d approximately 5f approximately 5h. Esters 5b, 5c, and 5e were tested in vivo against various human carcinomas in nude mice grown as xenografts. Only 5b and 5c showed a significant antitumor activity. Particularly, ester 5b demonstrated an antitumor activity against a broad spectrum of human carcinomas including breast, lung, colon, pancreas, stomach, ovarian, and melanoma, etc.
CONCLUSION
These esters act like prodrugs of their parental 9-nitrocamptothecin. High drug doses need to be administered to animals in order to inhibit growth, and induce regression, of human tumor xenografts in nude mice. These compounds may be developed into potent anticancer drugs due to their low toxicity.
Topics: Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Esters; HL-60 Cells; Humans; Mice; Mice, Nude; Molecular Structure; Prodrugs; Structure-Activity Relationship; U937 Cells; Xenograft Model Antitumor Assays
PubMed: 12546717
DOI: No ID Found -
PloS One 2011Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with...
BACKGROUND
Hepatocellular carcinoma (HCC) is the third most common cause of cancer related mortality worldwide. 9-Nitrocamptothecin (9NC) is a potent topoisomerase-I inhibitor with strong anticancer effect. To increase the solubility and stability, we synthesized a novel 9NC loaded liposomes (9NC-LP) via incorporating 9NC into liposomes. In the present study, we determined the effects of 9NC and 9NC-LP on in vitro and in vivo, and the underlying mechanisms.
METHODOLOGY/PRINCIPAL FINDINGS
We first analyzed the characteristics of 9NC-LP. Then we compared the effects of 9NC and 9NC-LP on the proliferation and apoptosis of HepG2, Bel-7402, Hep3B and L02 cells in vitro. We also investigated their anticancer properties in nude mice bearing HCC xenograft in vivo. 9NC-LP has a uniform size (around 190 nm) and zeta potential (∼-11 mV), and exhibited a steady sustained-release pattern profile in vitro. Both 9NC and 9NC-LP could cause cell cycle arrest and apoptosis in a dose-dependent and p53-dependent manner. However, this effect was not ubiquitous in all cell lines. Exposure to 9NC-LP led to increased expression of p53, p21, p27, Bax, caspase-3, caspase-8, caspase-9 and apoptosis-inducing factor, mitochondrion-associated 1 and decreased expression of Bcl-2, cyclin E, cyclin A, Cdk2 and cyclin D1. Furthermore, 9NC-LP exhibited a more potent antiproliferative effect and less side effects in vivo. Western blot analysis of the xenograft tumors in nude mice showed similar changes in protein expression in vivo.
CONCLUSIONS/SIGNIFICANCE
In conclusion, 9NC and 9NC-LP can inhibit HCC growth via cell cycle arrest and induction of apoptosis. 9NC-LP has a more potent anti-tumor effect and fewer side effects in vivo, which means it is a promising reagent for cancer therapy via intravenous administration.
Topics: Animals; Antineoplastic Agents; Apoptosis; Camptothecin; Carcinoma, Hepatocellular; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Drug Stability; Female; Gene Expression Regulation, Neoplastic; Humans; Liposomes; Liver Neoplasms; Mice; Solubility; Ultrasonics; Water; Xenograft Model Antitumor Assays
PubMed: 21695227
DOI: 10.1371/journal.pone.0021064 -
Bulletin Du Cancer Mar 2003Cancer occurs and it is life that runs off the rails. To restore the melody, the oncologist can use an array of pharmacological instruments which he needs to tune...
Cancer occurs and it is life that runs off the rails. To restore the melody, the oncologist can use an array of pharmacological instruments which he needs to tune optimally to reach the maximal efficacy. Camptothecin derivatives, inhibitors of topoisomerase I, represent an essential family of the chemotherapeutic arsenal. Topotecan and irinotecan have been used in the clinic for a number of years, but other potent analogues are appearing and broaden the range of topoisomerase I poisons. In this review, we present the main molecular characteristics of the second generation of camptothecins (lurtotecan, exatecan, rubitecan, silatecan). The future is also evoked with camptothecin derivatives bearing a modified lactone ring, in particular the homocamptothecins and the drug diflomotecan, which shows promise as an anticancer. The camptothecin partition is disclosed here.
Topics: Antineoplastic Agents; Camptothecin; Enzyme Inhibitors; Irinotecan; Music; Neoplasms; Organosilicon Compounds; Structure-Activity Relationship; Topoisomerase I Inhibitors; Topotecan
PubMed: 12801826
DOI: No ID Found