-
Molecules (Basel, Switzerland) Oct 2017Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of...
Low efficiency of chemotherapy in ovarian cancer results from the development of drug resistance. Cisplatin (CIS) and topotecan (TOP) are drugs used in chemotherapy of this cancer. We analyzed the development of CIS and TOP resistance in ovarian cancer cell lines. Incubation of drug sensitive cell lines (W1 and A2780) with cytostatic drugs was used to determine the primary response to CIS and TOP. Quantitative polymerase chain reaction (Q-PCR) was performed to measure the expression levels of the genes. We observed decreased expression of the gene in all resistant cell lines. We observed overexpression of the and genes in TOP-resistant cell lines. Increased expression of the gene was also observed in CIS-resistant A2780 sublines. Overexpression of the gene was observed in CIS- and TOP-resistant A2780 sublines. A short time of exposure to CIS led to increased expression of the gene in the W1 and A2780 cell lines and increased expression of the gene in the A2780 cell line. A short time of exposure to TOP led to increased expression of the and genes in both sensitive cell lines, increased expression of the gene in the A2780 cell line and downregulation of the gene in the W1 cell line. Our results suggest that changes in expression of the , and genes may be related to both CIS and TOP resistance. Increased expression of the gene seems to be important only in TOP resistance.
Topics: Cell Line, Tumor; Cisplatin; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Ovarian Neoplasms; S100 Proteins; Topotecan
PubMed: 29027969
DOI: 10.3390/molecules22101717 -
The Cochrane Database of Systematic... Apr 2017Patients with newly diagnosed high-risk (HR) neuroblastoma (NBL) still have a poor outcome, despite multi-modality intensive therapy. This poor outcome necessitates the... (Review)
Review
BACKGROUND
Patients with newly diagnosed high-risk (HR) neuroblastoma (NBL) still have a poor outcome, despite multi-modality intensive therapy. This poor outcome necessitates the search for new therapies, such as treatment with I-meta-iodobenzylguanidine (I-MIBG).
OBJECTIVES
To assess the efficacy and adverse effects of I-MIBG therapy in patients with newly diagnosed HR NBL.
SEARCH METHODS
We searched the following electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library 2016, Issue 3), MEDLINE (PubMed) (1945 to 25 April 2016) and Embase (Ovid) (1980 to 25 April 2016). In addition, we handsearched reference lists of relevant articles and reviews. We also assessed the conference proceedings of the International Society for Paediatric Oncology, Advances in Neuroblastoma Research and the American Society of Clinical Oncology; all from 2010 up to and including 2015. We scanned the International Standard Randomized Controlled Trial Number (ISRCTN) Register (www.isrctn.com) and the National Institutes of Health Register for ongoing trials (www.clinicaltrials.gov) on 13 April 2016.
SELECTION CRITERIA
Randomised controlled trials (RCTs), controlled clinical trials (CCTs), non-randomised single-arm trials with historical controls and cohort studies examining the efficacy of I-MIBG therapy in 10 or more patients with newly diagnosed HR NBL.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed the study selection, risk of bias assessment and data extraction.
MAIN RESULTS
We identified two eligible cohort studies including 60 children with newly diagnosed HR NBL. All studies had methodological limitations, with regard to both internal (risk of bias) and external validity. As the studies were not comparable with regard to prognostic factors and treatment (and often used different outcome definitions), pooling of results was not possible. In one study, the objective response rate (ORR) was 73% after surgery; the median overall survival was 15 months (95% confidence interval (CI) 7 to 23); five-year overall survival was 14.6%; median event-free survival was 10 months (95% CI 7 to 13); and five-year event-free survival was 12.2%. In the other study, the ORR was 56% after myeloablative therapy and autologous stem cell transplantation; 10-year overall survival was 6.25%; and event-free survival was not reported. With regard to short-term adverse effects, one study showed a prevalence of 2% (95% CI 0% to 13%; best-case scenario) for death due to myelosuppression. After the first cycle of I-MIBG therapy in one study, platelet toxicity occurred in 38% (95% CI 18% to 61%), neutrophil toxicity in 50% (95% CI 28% to 72%) and haemoglobin toxicity in 69% (95% CI 44% to 86%); after the second cycle this was 60% (95% CI 36% to 80%) for platelets and neutrophils and 53% (95% CI 30% to 75%) for haemoglobin. In one study, the prevalence of hepatic toxicity during or within four weeks after last the MIBG treatment was 0% (95% CI 0% to 9%; best-case scenario). Neither study reported cardiovascular toxicity and sialoadenitis. One study assessed long-term adverse events in some of the children: there was elevated plasma thyroid-stimulating hormone in 45% (95% CI 27% to 65%) of children; in all children, free T4 was within the age-related normal range (0%, 95% CI 0% to 15%). There were no secondary malignancies observed (0%, 95% CI 0% to 9%), but only five children survived more than four years.
AUTHORS' CONCLUSIONS
We identified no RCTs or CCTs comparing the effectiveness of treatment including I-MIBG therapy versus treatment not including I-MIBG therapy in patients with newly diagnosed HR NBL. We found two small observational studies including chilren. They had high risk of bias, and not all relevant outcome results were available. Based on the currently available evidence, we cannot make recommendations for the use of I-MIBG therapy in patients with newly diagnosed HR NBL in clinical practice. More high-quality research is needed.
Topics: 3-Iodobenzylguanidine; Adolescent; Antineoplastic Agents; Bone Marrow; Child; Child, Preschool; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Infant; Neuroblastoma; Observational Studies as Topic; Radiopharmaceuticals; Thyroid Diseases; Topotecan
PubMed: 28429876
DOI: 10.1002/14651858.CD010349.pub2 -
Molecules (Basel, Switzerland) Dec 2022The use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is...
The use of cancer chemotherapy sensitizers is a promising approach to induce the effect of clinically used anticancer treatments. One of the interesting targets is Tyrosyl-DNA Phosphodiesterase 1 (Tdp1), a DNA-repair enzyme, that may prevent the action of clinical Topoisomerase 1 (Top1) inhibitors, such as topotecan (Tpc). Tdp1 eliminates covalent Top1-DNA (Top1c) complexes that appear under the action of topotecan and determines the cytotoxic effect of this drug. We hypothesize that Tdp1 inhibition would sensitize cells towards the effect of Tpc. Herein, we report the synthesis and study of lipophilic derivatives of purine nucleosides that efficiently suppress Tdp1 activity, with IC values in the 0.3-22.0 μM range. We also showed that this compound class can enhance DNA damage induced by topotecan in vitro by Comet assay on human cell lines HeLa and potentiate the antitumor effect of topotecan in vivo on a mice ascitic Krebs-2 carcinoma model. Thereby, this type of compound may be useful to develop drugs, that sensitize the effect of topotecan and reduce the required dose and, as a result, side effects.
Topics: Animals; Mice; Humans; Topotecan; Phosphoric Diester Hydrolases; Phosphodiesterase Inhibitors; Purine Nucleosides; Structure-Activity Relationship; Topoisomerase I Inhibitors; Esterases; DNA Damage; DNA; DNA Topoisomerases, Type I
PubMed: 36615517
DOI: 10.3390/molecules28010323 -
Oncology Reports Dec 2023Acute myeloid leukemia (AML) is a common type of acute leukemia in adults and relapse is one of the main reasons for treatment failure. FLT3‑ITD mutations are...
Acute myeloid leukemia (AML) is a common type of acute leukemia in adults and relapse is one of the main reasons for treatment failure. FLT3‑ITD mutations are associated with poor prognosis, short disease‑free progression survival and high relapse rates in patients with AML. STAT5 is activated by FLT3‑ITD and drives the pathogenesis of AML. STAT5 activation is usually a hallmark of hematologic malignancies and occurs in ~70% of patients with AML. Moreover, STAT5 is a key molecule which regulates hematopoiesis, and its high expression is closely associated with drug resistance, thus direct targeting of STAT5 for AML is of great clinical value. The present study introduces a new small‑molecule inhibitor that targets STAT5, presenting a promising approach for AML therapy. A high throughput fluorescence polarization (FP) screening system for STAT5 was designed and established, and used to screen an existing compound library to obtain the highly active small molecule inhibitor, topotecan hydrochloride. Topotecan hydrochloride was demonstrated to be an effective inhibitor of STAT5 by molecular docking prediction and cellular thermal shift assay. Topotecan hydrochloride bound to STAT5, inhibiting its dimerization, phosphorylation and transcription of specific target genes. The compound exhibits cellular activity at the nanomolar level and significantly inhibits the proliferation of human AML cell lines and FLT3‑ITD AML cells. Furthermore, topotecan hydrochloride has the potential to exert an anti‑tumor effect . Overall, topotecan hydrochloride offers a new opportunity for the treatment of AML and other hematologic malignancies by directly targeting STAT5.
Topics: Humans; Topotecan; STAT5 Transcription Factor; Molecular Docking Simulation; Leukemia, Myeloid, Acute; Recurrence; Hematologic Neoplasms
PubMed: 37830151
DOI: 10.3892/or.2023.8645 -
The Oncologist 2002The conventional front-line chemotherapy strategy for advanced epithelial ovarian carcinoma has become adjuvant administration of platinum (carboplatin and cisplatin),... (Review)
Review
The conventional front-line chemotherapy strategy for advanced epithelial ovarian carcinoma has become adjuvant administration of platinum (carboplatin and cisplatin), either alone or, most often, in combination with a taxane. However, a number of active agents have been identified in phase II/III trials of second-line and salvage ovarian cancer patients that may augment this front-line strategy. One agent, topotecan, has antitumor activity comparable with paclitaxel in patients with recurrent ovarian cancer and is an established treatment in second-line or salvage settings. Additionally, its mechanism of action is different from paclitaxel and is nonoverlapping. These properties, coupled with the in vitro synergy observed in tumor models among topotecan, paclitaxel, and platinum, have provided the rationale for investigators to examine topotecan in front-line ovarian cancer therapy. A number of strategies for incorporating topotecan into front-line therapy are under active investigation, including the replacement of paclitaxel with topotecan, a triplet regimen with cisplatin or carboplatin and paclitaxel, a consolidation regimen consisting of several courses of a platinum agent and paclitaxel followed by several courses of topotecan, and a sequential doublet regimen in which patients receive platinum in every course as part of a doublet with alternating or sequential topotecan and paclitaxel. Preliminary data from ongoing clinical trials of these new regimens show favorable response rates and generally manageable toxicity profiles. This review summarizes the preliminary clinical findings associated with the four strategies and outlines ongoing and future randomized studies of topotecan in front-line ovarian cancer.
Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Ovarian Neoplasms; Salvage Therapy; Topotecan
PubMed: 12324633
DOI: 10.1634/theoncologist.7-suppl_5-46 -
Medicine Apr 2018We retrospectively reviewed outcomes of treatments with cisplatin and topotecan in patients with previously-treated uterine cervix cancer.We analyzed the medical records...
We retrospectively reviewed outcomes of treatments with cisplatin and topotecan in patients with previously-treated uterine cervix cancer.We analyzed the medical records of patients with advanced (stage IVB) or recurrent or persistent squamous or non-squamous cell carcinoma of the cervix, who were treated with cisplatin and topotecan as a second-line chemotherapy between January 2000 and December 2015. The patients were treated with a combination of cisplatin (50 mg/m for 1 day) and topotecan (0.75 mg/m for 3 days) once every 3 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and non-responder groups (responders showed at least a partial response to prior systemic chemotherapy).Thirty-nine patients with a median age of 47 years (range, 32-73 years) were treated with cisplatin and topotecan. The median PFS was 4.6 months (95% confidence interval [CI], 1.2-7.9 months) and the median OS was 14.1 months (95% CI, 10.0-18.2 months). The overall response rate (ORR) was 30.8%, and the disease control rate was 56.4%. The ORR was significantly better in the responder group compared with the non-responder group (50.0% vs 10.5%; P = .008). All patients reported some grade of hematological toxicity. The most frequently encountered toxicity was anemia, with a rate of 59.7% for any grade and 13.2% for grade 3 or 4.The combination of cisplatin and topotecan was effective as second-line chemotherapy in patients with advanced/recurrent uterine cervix cancer.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Disease-Free Survival; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Retrospective Studies; Topotecan; Treatment Outcome; Uterine Cervical Neoplasms
PubMed: 29620661
DOI: 10.1097/MD.0000000000010340 -
British Journal of Cancer Aug 2021Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have...
BACKGROUND
Pazopanib is active in refractory soft-tissue sarcoma (STS) and significantly prolongs PFS. Prior studies of combinations of metronomic topotecan with pazopanib have indicated preclinical evidence of response in patients with sarcoma.
METHODS
This prospective, single arm, phase II study evaluated the efficacy of the combination of pazopanib with topotecan in patients with metastatic or unresectable non-adipocytic STS. Furthermore, it incorporated exploratory arms for osteosarcoma and liposarcoma. The primary endpoint was progression-free rate at 12 weeks in the non-adipocytic STS cohort.
RESULTS
57.5% of patients in the non-adipocytic STS cohort were progression free at 12 weeks, which did not meet the primary endpoint of the study (66%). The exploratory osteosarcoma cohort exceeded previously established phase II trial comparator data benchmark of 12% with a PFR at 12 weeks of 69.55%. Treatment with the combination of pazopanib and topotecan was accompanied by a grade 3 or 4 toxicities in most patients.
CONCLUSIONS
In this prospective trial in refractory metastatic or unresectable STS and osteosarcoma, the combination of pazopanib with topotecan did not meet its primary endpoint of progression-free rate at 12 weeks. The combination of pazopanib with topotecan was associated with a high degree of toxicity.
Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Administration Schedule; Humans; Indazoles; Male; Middle Aged; Neoplasm Metastasis; Osteosarcoma; Prospective Studies; Pyrimidines; Sarcoma; Sulfonamides; Topotecan; Treatment Outcome; Young Adult
PubMed: 34050255
DOI: 10.1038/s41416-021-01448-0 -
European Journal of Cancer (Oxford,... Sep 1998Used for centuries in traditional Chinese medicine, camptothecin was rediscovered in the 1950s during a search for compounds that could be used as a source for steroid... (Review)
Review
Used for centuries in traditional Chinese medicine, camptothecin was rediscovered in the 1950s during a search for compounds that could be used as a source for steroid synthesis. Due to its limited water solubility, a sodium salt was used in the early clinical trials. The severe toxicity and erratic absorption relegated this compound to the research laboratory until the 1980s when the topoisomerase enzyme was identified as the cellular target of camptothecin, the topoisomerase enzyme was found to be overexpressed in cancer cells and a structure-activity relationship was determined for camptothecin. These new developments brought the camptothecins back to the clinical setting for further testing. The various analogues that have been most studied to date include: irinotecan (CPT-11), and its derivative SN-38, topotecan, and 9-aminocamptothecin. Numerous trials have been conducted in an attempt to establish the efficacy in various tumour types, to determine the dose-limiting toxicity and to define the optimal schedule of administration. It seems that large doses of these drugs given on intermittent schedules are not effective. Our hypothesis is that the camptothecins require a prolonged schedule of administration given continuously at low doses or frequent intermittent dosing schedules to be most effective. With these schedules, normal haematopoietic cells and mucosal progenitor cells with low topoisomerase I levels may be spared, while efficacy is preserved.
Topics: Antineoplastic Agents, Phytogenic; Camptothecin; DNA Topoisomerases, Type I; Drug Administration Schedule; Humans; Irinotecan; Neoplasms; Topotecan
PubMed: 9893620
DOI: 10.1016/s0959-8049(98)00229-9 -
Oncotarget Apr 2017To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a...
PURPOSE
To determine the maximum tolerated dose (MTD), toxicities, and pharmacodynamics effects of sirolimus combined with oral metronomic topotecan and cyclophosphamide in a pediatric population.
MATERIALS AND METHODS
Patients who were 1 to 30 years of age with relapsed/refractory solid tumors (including CNS) were eligible. Patients received daily oral sirolimus and cyclophosphamide (25-50 mg/m2/dose) on days 1-21 and oral topotecan (0.8 mg/m2/dose) on days 1-14 in 28-day cycles. Sirolimus steady-state plasma trough concentrations of 3-7.9 ng/mL and 8-12.0 ng/mL were evaluated, with dose escalation based on a 3+3 phase 1 design. Biomarkers of angiogenesis were also evaluated.
RESULTS
Twenty-one patients were treated (median age 18 years; range 9-30). Dose-limiting toxicities included myelosuppression, ALT elevation, stomatitis, and hypertriglyceridemia. The MTD was sirolimus with trough goal of 8-12.0 ng/mL; cyclophosphamide 25 mg/m2/dose; and topotecan 0.8 mg/m2/dose. No objective responses were observed. Four patients had prolonged stable disease > 4 cycles (range 4-12). Correlative biomarker analyses demonstrated reductions in thrombospondin-1 (p=0.043) and soluble vascular endothelial growth factor receptor-2 plasma concentrations at 21 days compared to baseline.
CONCLUSIONS
The combination of oral sirolimus, topotecan, and cyclophosphamide was well tolerated and biomarker studies demonstrated modulation of angiogenic pathways with this regimen.
Topics: Adolescent; Adult; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Child; Cyclophosphamide; Female; Humans; Male; Neoplasm Recurrence, Local; Neoplasms; Sirolimus; Topotecan; Young Adult
PubMed: 27793021
DOI: 10.18632/oncotarget.12904 -
The Oncologist 2002Carcinomas of the uterine cervix and corpus are significant causes of morbidity and mortality among women in the U.S. and are expected to contribute 10,700 deaths in... (Review)
Review
Carcinomas of the uterine cervix and corpus are significant causes of morbidity and mortality among women in the U.S. and are expected to contribute 10,700 deaths in 2002. Despite the widespread use of cytologic screening and improvements in early diagnosis, mortality rates have changed little over the past 25 years, and the management of cervical and uterine cancers remains a significant unmet medical need. Currently available modalities, including radiotherapy and cisplatin-based chemotherapy, provide suboptimal control of disease, and there are no effective treatments for recurrent disease. The antitumor activity and tolerability of a number of novel agents, including topoisomerase I inhibitors, vinca alkaloids, taxanes, and gemcitabine, have been of considerable interest in treatment of these cancers. This review discusses current trends in the treatment of cervical and endometrial carcinomas, focusing on the potential role of topotecan in the treatment of non-ovarian gynecologic malignancies.
Topics: Antineoplastic Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Therapy, Combination; Endometrial Neoplasms; Enzyme Inhibitors; Female; Humans; Neoplasm Recurrence, Local; Neoplasm Staging; Salvage Therapy; Topotecan; Uterine Cervical Neoplasms
PubMed: 12324632
DOI: 10.1634/theoncologist.7-suppl_5-36