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"An antineoplastic agent used to treat ovarian cancer. It works by inhibiting DNA TOPOISOMERASES, TYPE I." (MeSH 2013)

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Latest Research Publications

Web Resources: Topotecan (6 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Winter U, Aschero R, Fuentes F, et al.
Tridimensional Retinoblastoma Cultures as Vitreous Seeds Models for Live-Cell Imaging of Chemotherapy Penetration.
Int J Mol Sci. 2019; 20(5) [PubMed] Free Access to Full Article Related Publications
A preclinical model could aid in understanding retinoblastoma vitreous seeds behavior, drug penetration, and response to chemotherapy to optimize patient treatment. Our aim was to develop a tridimensional in vitro model of retinoblastoma vitreous seeds to assess chemotherapy penetration by means of live-cell imaging. Cell cultures from patients with retinoblastoma who underwent upfront enucleation were established and thoroughly characterized for authentication of human tumor origin. The correlation of the in vitro tridimensional structures resembling human spheres and dusts vitreous seeds was established. Confocal microscopy was used to quantify real-time fluorescence of topotecan as a measure of its penetration into different sizes of spheres. Cell viability was determined after chemotherapy penetration. The in vitro spheres and dusts models were able to recapitulate the morphology, phenotype, and genotype of patient vitreous seeds. The larger the size of the spheres, the longer the time required for the drug to fully penetrate into the core (

Rojanaporn D, Chanthanaphak E, Boonyaopas R, et al.
Intra-Arterial Chemotherapy for Retinoblastoma: 8-Year Experience from a Tertiary Referral Institute in Thailand.
Asia Pac J Ophthalmol (Phila). 2019 May-Jun; 8(3):211-217 [PubMed] Related Publications
PURPOSE: To study the safety and efficacy of intra-arterial chemotherapy (IAC) as a treatment for intraocular retinoblastoma in Thailand.
DESIGN: Retrospective, interventional case series.
METHODS: In this study, IAC was performed as primary or secondary treatment for patients with intraocular retinoblastoma using melphalan with or without additional topotecan or carboplatin. Survival rate, globe salvage rate, and treatment complications were recorded and analyzed.
RESULTS: Of 27 eyes of 26 patients with retinoblastoma, 7 (26%) had IAC as primary treatment and 20 (74%) had IAC as secondary treatment. The eyes were classified by International Classification of Retinoblastoma (ICRB) as group B (n = 3, 11%), group C (n = 1, 4%), group D (n = 12, 44%), and group E (n = 11, 41%). Catheterization was successful in 75 (94%) of 80 sessions. The median number of IAC sessions was 3 (range, 1-7). At a mean follow-up of 32 months (range, 3-95 months), the overall globe salvage rate was 52%, with 100% in groups B and C, 75% in group D, and 9% in group E. Complications of IAC included occlusive vasculopathy (n = 4, 15%), vitreous hemorrhage (n = 3, 11%), retinal artery precipitation (n = 2, 7%), strabismus (n = 2, 7%), and transient ischemic attack (n = 1, 4%). The overall survival rate was 96% (n = 25).
CONCLUSIONS: Our experience suggests that IAC is a safe and effective treatment for patients with ICRB group B, C, D, and some group E retinoblastoma. Careful patient selection and experienced surgeons are critical for achieving the best treatment outcome.

Wang L, Liu Y, Zhao TL, et al.
Topotecan induces apoptosis via ASCT2 mediated oxidative stress in gastric cancer.
Phytomedicine. 2019; 57:117-128 [PubMed] Related Publications
BACKGROUND: Topotecan (TPT) is a Topo I inhibitor and shows obvious anti-cancer effects on gastric cancer. Cancer cells reprogram their metabolic pathways to increase nutrients uptake, which has already been a hallmark of cancer. But the effect of TPT on metabolism in gastric cancer remains unknown.
PURPOSE: To investigate the effect of TPT on metabolism in gastric cancer.
METHODS: ATP production was measured by ATP Assay kit. Glucose and glutamine uptake were measured by Glucose (HK) Assay Kit and Glutamine/Glutamate Determination Kit respectively. To detect glutathione (GSH) concentration and reactive oxygen species (ROS) generation, GSH and GSSG Assay Kit and ROS Assay Kit were adopted. Apoptosis rates, mitochondrial membrane potential (MMP) were determined by flow cytometry and protein levels were analyzed by immumohistochemical staining and western blotting.
RESULTS: TPT increased ATP production. TPT promoted glucose uptake possibly via up-regulation of hexokinase 2 (HK2) or glucose transporter 1 (GLUT1) expression, while decreased glutamine uptake by down-regulation of ASCT2 expression. ASCT2 inhibitor GPNA and ASCT2 knockdown significantly suppressed the growth of gastric cancer cells. Inhibition of ASCT2 reduced glutamine uptake which led to decreased production of GSH and increased ROS level. ASCT2 knockdown induced apoptosis via the mitochondrial pathway and weakened anti-cancer effect of TPT.
CONCLUSION: TPT inhibits glutamine uptake via down-regulation of ASCT2 which causes oxidative stress and induces apoptosis through the mitochondrial pathway. Moreover, TPT inhibits proliferation partially via ASCT2. These observations reveal a previously undescribed mechanism of ASCT2 regulated gastric cancer proliferation and demonstrate ASCT2 is a potential anti-cancer target of TPT.

Neshasteh-Riz A, Eyvazzadeh N, Rostami A, Azzizolahi E
Cytogenetic damage from hyperthermia,6 MV X-rays, and topotecan in glioblastoma spheroids, simultaneously, and separately.
J Cancer Res Ther. 2018 Oct-Dec; 14(6):1273-1278 [PubMed] Related Publications
Purpose: Glioblastoma multiform (GBM) is one of the most common brain tumors. Surgery, radiation therapy, hyperthermia, and chemotherapy are the most common treatments for brain tumors such as GBM. This study investigated the cytogenetic damage caused by hyperthermia, radiation (6 MV-X-rays), and topotecan in glioma spheroids, simultaneously and separately.
Materials and Methods: Human glioblastoma cell line was cultured to form spheroids 350 μm in diameter that were arranged in eight groups and coded as follows: control, T: topotecan, H: hyperthermia, T + H: topotecan + hypertermia, X 1-10: X-ray with 1-10 fraction irradiation, H + X (1-10): hypertermia + X-ray with 1-10 fraction irradiation, T + X (1-10): topotecan + X-ray with 1-10 fraction irradiation, and H + T + X (1-10): hypertermia + topotecan + X-ray with 1-10 fraction irradiation. DNA damage was then evaluated using clonogenic assay.
Results: The effect of combined treatment with X + H + T was greater than the sum of the effects in other groups. In H + T + X group, failure to form colonies was observed in the seventh session.
Conclusion: Use of X + H + T combination therapy significantly increased cell death and possibly improved the treatment. This suggests that the synergistic effect of different therapeutic methods increased cell death in glioblastoma tumor cells and reduced the necessary dose of radiation in the treatment of tumor in radiation therapy.

Sthapit PR, Rao R, Honavar SG
Periocular topotecan for vitreous seeds in retinoblastoma.
Indian J Ophthalmol. 2018; 66(12):1833-1838 [PubMed] Free Access to Full Article Related Publications
Purpose: Refractory or recurrent vitreous seeds account for a large proportion of failure of eye salvage in retinoblastoma. The purpose of this study is to evaluate the efficacy of periocular topotecan (POT) in the management of vitreous seeds in retinoblastoma.
Methods: Retrospective, interventional study of patients with retinoblastoma with vitreous seeds who received POT concurrent with intravenous chemotherapy (IVC).
Results: Thirty-eight eyes of 35 patients received POT. Five eyes (13%) belonged to International Classification of Retinoblastoma group C, 23 eyes (61%) belonged to group D, and 10 eyes (26%) belonged to group E. Primary treatment included IVC with a combination of carboplatin, etoposide, and vincristine for a mean of 6 cycles (median 6; range 6-9). Concurrent to IVC from the fourth cycle onward, all patients received POT. Focal vitreous seeds were present in 20 eyes (53%) which received a mean of 3 injections (median 3; range 1-7). Diffuse vitreous seeds were present in 18 eyes (47%) which received a mean of 4 injections (median 5; range 1-7). At a mean follow-up of 8.5 months (median 5 months; range 1-15 months), regression of focal and diffuse vitreous seeds was achieved in 16 eyes (80%) and 8 eyes (44%), respectively. In all, 24 eyes (63%) had complete remission of vitreous seeds with POT given concurrently with IVC. Eye salvage was possible in 19 eyes (95%) with focal vitreous seeds and 12 eyes (68%) with diffuse VS. Enucleation was necessary for persistent vitreous seeds and viable tumor in five eyes (13%), viable tumor alone in one eye (0.02%), and recurrent vitreous seeds in one eye (0.02%). None of the patients developed systemic metastasis.
Conclusion: POT administered concurrent with IVC is safe and effective in the initial management of vitreous seeds.

Zakharenko AL, Luzina OA, Sokolov DN, et al.
Novel tyrosyl-DNA phosphodiesterase 1 inhibitors enhance the therapeutic impact of topoteсan on in vivo tumor models.
Eur J Med Chem. 2019; 161:581-593 [PubMed] Related Publications
The druggability of the tyrosyl-DNA phosphodiesterase 1 (Tdp1) enzyme was investigated in conjunction with topoisomerase 1 inhibition. A novel class of thiazole, aminothiazole and hydrazonothiazole usnic acid derivatives was synthesized and evaluated as Tdp1 inhibitors and their ability to sensitize tumors to topotecan, a topoisomerase inhibitor in clinical use. Of all the compounds tested, four hydrazinothiazole derivatives, 20c, 20d, 20h and 20i, inhibited the enzyme in the nanomolar range. The activity of the compounds was verified by affinity experiments as well as supported by molecular modelling. The most effective Tdp1 inhibitor, 20d, was ton-toxic and increased the effect of topotecan both in vitro and in vivo in the Lewis lung carcinoma model. Furthermore, 20d showed significant increase in the antitumor and antimetastatic effect of topotecan in mice. The results presented here justify compound 20d to be considered as a drug lead for antitumor therapy.

Wang L, Han M, Zhao J, et al.
Intra-arterial chemotherapy for unilateral advanced intraocular retinoblastoma: Results and short-term complications.
Medicine (Baltimore). 2018; 97(42):e12676 [PubMed] Free Access to Full Article Related Publications
Intra-arterial chemotherapy (IAC) has become an essential technique for the management of advanced intraocular retinoblastoma (RB). In this study, the aim of this article is to describe the clinical results and the short-term complications of IAC performed in our hospital.We retrospectively analyzed patients with newly diagnosed unilateral advanced intraocular (group D or E) RB undergoing IAC from October 2016 to December 2017 in our hospital. We recorded the data including age, gender, cycles of IAC, pathway of arteries approached (ophthalmic artery or middle meningeal artery), ocular and systematic complications, globe salvage.Sixty-one patients underwent IAC performing 189 procedures with a median of 3.1 sessions per eye (range, 1-5 sessions). The overall globe salvage rate is 78.7% (Group D (84.2%), and Group E (69.6%) and followed-up. Short-term ocular complications include eyelid edema (15 cases), ptosis (5 cases), forehead congestion (3 cases), retina hemorrhage (5 cases), choroid atrophy (2 cases), phthisis bulbi (1 case), bradycardia and hypotension during the procedure (7cases), myelosuppressions (6 cases), and nausea and vomiting (5cases).IAC is safe and effective for the treatment of unilateral advanced intraocular RB with a very low complication rate.

Imai H, Yamada Y, Minemura H, et al.
Topotecan monotherapy for the treatment of relapsed small cell lung cancer in elderly patients: A retrospective analysis.
Thorac Cancer. 2018; 9(12):1699-1706 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Topotecan is one of the most active chemotherapeutic drugs for small cell lung cancer (SCLC). However, its efficacy in elderly patients with SCLC has not been validated. This study evaluated the feasibility and efficacy of topotecan monotherapy in elderly patients with relapsed SCLC.
METHODS: Between January 2000 and March 2017, 43 patients aged ≥ 70 years received topotecan monotherapy for relapsed SCLC at four institutions. The clinical outcomes and adverse events of treatment were retrospectively analyzed.
RESULTS: Twenty-nine patients (median age 75 years; range: 70-83 years) had sensitive-type relapse, while 14 (median age 78 years; range: 71-82 years) had refractory relapse. The median number of treatment cycles was two (range: 1-6). The response rate was 7.0% (10.3% and 0% in sensitive and refractory patients, respectively), while the disease control rate was 23.2% (20.6% and 42.8% in sensitive and refractory patients, respectively). Median progression-free survival was 1.9 months in sensitive patients and 1.4 months in refractory patients (P = 0.87). The median survival time from the start of topotecan therapy was 5.5 months in sensitive patients and 4.0 months in refractory patients (P = 0.64). Grade ≥ 3 hematological toxicities were as follows: leukopenia, 37.2%; neutropenia, 51.1%; anemia, 0%; thrombocytopenia, 32.5%; and febrile neutropenia, 9.3%. No treatment-related deaths occurred.
CONCLUSION: Although hematological toxicities (particularly neutropenia) were severe, topotecan showed favorable disease control in both sensitive and refractory patients. Topotecan may thus be a preferred treatment for elderly patients with relapsed SCLC.

Sterzyńska K, Klejewski A, Wojtowicz K, et al.
The Role of Matrix Gla Protein (MGP) Expression in Paclitaxel and Topotecan Resistant Ovarian Cancer Cell Lines.
Int J Mol Sci. 2018; 19(10) [PubMed] Free Access to Full Article Related Publications
The major cause of ovarian cancer treatment failure in cancer patients is inherent or acquired during treatment drug resistance of cancer. Matrix Gla protein (MGP) is a secreted, non-collagenous extracellular matrix protein involved in inhibition of tissue calcification. Recently, MGP expression was related to cellular differentiation and tumor progression. A detailed MGP expression analysis in sensitive (A2780) and resistant to paclitaxel (PAC) (A2780PR) and topotecan (TOP) (A2780TR) ovarian cancer cell lines and their corresponding media was performed.

Compostella A, Affinita MC, Casanova M, et al.
Topotecan/carboplatin regimen for refractory/recurrent rhabdomyosarcoma in children: Report from the AIEOP Soft Tissue Sarcoma Committee.
Tumori. 2019; 105(2):138-143 [PubMed] Related Publications
INTRODUCTION: From 2002 to 2011, the Italian Soft Tissue Sarcoma Committee explored a combination of topotecan and carboplatin as a second-line strategy for children with resistant or relapsing rhabdomyosarcoma.
METHODS: Patients received two blocks of topotecan 2 mg/m
RESULTS: A total of 38 patients were included in this study: 18/38 had alveolar rhabdomyosarcoma (RMS), 10/38 had metastatic disease at diagnosis, 8/38 had tumor progression during first-line chemotherapy, 21/38 had locoregional relapses, and 9/38 had distant relapses. Thirty-two patients could be assessed for tumor response to topotecan-carboplatin, and 9 (28%) showed a complete or partial response. Twenty-four patients experienced grade IV hematologic toxicity, while transient grade 1 tubulopathy, grade 3 mucositis, transient grade 2 nephrotoxicity, and a grade 2 decline in cardiac function occurred in one patient each. The 5-year overall and progression-free survival rates were 17% and 14%, respectively.
CONCLUSION: the prognosis for children with resistant or relapsing RMS remains unsatisfactory. The topotecan-carboplatin regimen was well-tolerated. Though in case of late relapse the response rate was similar to those reported for other regimes, the result achieved remains unsatisfactory. New approaches, possibly including target agents, seem more attractive for future studies.

Liu SV, Groshen SG, Kelly K, et al.
A phase I trial of topotecan plus tivantinib in patients with advanced solid tumors.
Cancer Chemother Pharmacol. 2018; 82(4):723-732 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: Tyrosine kinase inhibitors (TKI) that target MET signaling have shown promise in various types of cancer, including lung cancer. Combination strategies have been proposed and developed to increase their therapeutic index. Based on preclinical synergy between inhibition of MET and topoisomerase I, a phase I study was designed to explore the combination of topotecan with the MET TKI tivantinib.
METHODS: Eligible patients with advanced solid malignancies for which there was no known effective treatment received topotecan at doses of 1.0-1.5 mg/m
RESULTS: The trial included 18 patients, 17 of whom received treatment. At the planned doses, the combination of topotecan and tivantinib was not tolerable due to thrombocytopenia and neutropenia. The addition of G-CSF to attenuate neutropenia did not improve tolerability. Greater tivantinib exposure, assessed through pharmacokinetic analysis, was associated with greater toxicity. No responses were seen. MET phosphorylation was feasible in CTC, but no changes were seen with therapy.
CONCLUSIONS: The combination of topotecan and oral tivantinib was not tolerable in this patient population.

Qu W, Meng B, Yu Y, Wang S
Folic acid-conjugated mesoporous silica nanoparticles for enhanced therapeutic efficacy of topotecan in retina cancers.
Int J Nanomedicine. 2018; 13:4379-4389 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
In this study, topotecan-loaded mesoporous silica nanoparticles were prepared and surface conjugated with folic acid (FTMN) to enhance the therapeutic efficacy of topotecan for the treatment of retinoblastoma (RB) cancers. The particles were nano-sized and exhibited a sustained release of drug in the physiological conditions. The folic acid-conjugated nanoformulations exhibited a remarkable uptake in RB cells compared to that of non-targeted nanoparticles. These results clearly indicate that receptor-mediated endocytosis is the mechanism of cellular internalization. The greater cellular uptake of FTMN resulted in significantly higher cytotoxic effect in Y79 cancer cells compared to that of other formulations. The results were well corroborated with the live/dead assay and nuclear fragmentation assay. FTMN consistently induced apoptosis of cancer cells with an efficiency of ~58%. Our results clearly showed that nanoparticulate encapsulation of TPT exhibited superior anticancer efficacy in Y79 cancer cells compared to that of free drug or non-targeted nanoparticles. As expected, FTMN exhibited a remarkable reduction in the overall tumor volume compared to any other group with less presence of tumor cells in histology staining. Overall, folic acid-conjugated nanoparticulate system could provide an effective platform for RB treatment.

Chekerov R, Hilpert F, Mahner S, et al.
Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet Oncol. 2018; 19(9):1247-1258 [PubMed] Related Publications
BACKGROUND: Antiangiogenic therapy has known activity in ovarian cancer. The investigator-initiated randomised phase 2 TRIAS trial assessed the multi-kinase inhibitor sorafenib combined with topotecan and continued as maintenance therapy for platinum-resistant or platinum-refractory ovarian cancer.
METHODS: We did a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial at 20 sites in Germany. Patients (≥18 years) with platinum-resistant ovarian cancer previously treated with two or fewer chemotherapy lines for recurrent disease were stratified (first vs later relapse) in block sizes of four and randomly assigned (1:1) using a web-generated response system to topotecan (1·25 mg/m
FINDINGS: Between Jan 18, 2010, and Sept 19, 2013, 185 patients were enrolled, 174 of whom were randomly assigned: 85 to sorafenib and 89 to placebo. Two patients in the sorafenib group had serious adverse events before treatment and were excluded from analyses. 83 patients in the sorafenib group and 89 in the placebo group started treatment. Progression-free survival was significantly improved with sorafenib versus placebo (hazard ratio 0·60, 95% CI 0·43-0·83; p=0·0018). Median progression-free survival was 6·7 months (95% CI 5·8-7·6) with sorafenib versus 4·4 months (3·7-5·0) with placebo. The most common grade 3-4 adverse events were leucopenia (57 [69%] of 83 patients in the sorafenib group vs 47 [53%] of 89 in the placebo group), neutropenia (46 [55%] vs 48 [54%]), and thrombocytopenia (23 [28%] vs 20 [22%]). Serious adverse events occurred in 49 (59%) of 83 sorafenib-treated patients and 45 (51%) of 89 placebo-treated patients. Of these, events were fatal in four patients (5%) in the sorafenib group (dyspnoea and poor general condition, septic shock, ascites and dyspnoea, and sigma perforation) and seven (8%) in the placebo group (pulmonary embolism in two patients, disease progression in two patients, and one case each of sepsis with fever, pleural effusion, and tumour cachexia). Sorafenib was associated with increased incidences of grade 3 hand-foot skin reaction (three [13%] vs 0 patients) and grade 2 alopecia (24 [29%] vs 12 [13%]).
INTERPRETATION: Sorafenib, when given orally in combination with topotecan and continued as maintenance therapy, showed a statistically and clinically significant improvement in progression-free survival in women with platinum-resistant ovarian cancer. These encouraging results support the crucial role of antiangiogenesis as the treatment backbone in combination with chemotherapy, making this approach attractive for further assessment with other targeted strategies.
FUNDING: Bayer, Amgen, and GlaxoSmithKline.

Lopes-de-Araújo J, Reis S, Nunes C
Topotecan effect on the structure of normal and cancer plasma membrane lipid models: A multi-model approach.
Eur J Pharm Sci. 2018; 123:515-523 [PubMed] Related Publications
Topotecan is a relatively large, planar, asymmetric and polar molecule with a lactone moiety. In neutral or basic aqueous solutions, this ring opens forming the carboxylate form of Topotecan that is biologically inactive and uncapable of passively cross membranes. Nevertheless, despite this inability to cross membranes at this form, Topotecan may still be able to interact with phospholipid bilayers, disturbing them. In this context, phospholipid models, mimicking normal (DMPC at pH 7.4) and cancer cell lipid membranes (DMPC:DMPS (5:1) at pH 6.5), were used to assess structural modifications upon interaction with Topotecan. Langmuir isotherms of monolayers coupled with Brewster angle microscopy, differential scanning calorimetry of liposomes and X-ray scattering of small and wide angle of stacked multilayers were used as complementary techniques. The overall results show that the interaction of Topotecan with lipid membranes is deeply conditioned by their composition and that Topotecan seems to have a preferential interaction with the glycerol backbone of phosphatidylcholine phospholipids.

Lv C, Liu X, Zheng Q, et al.
Analysis of topoisomerase I expression and identification of predictive markers for efficacy of topotecan chemotherapy in small cell lung cancer.
Thorac Cancer. 2018; 9(9):1166-1173 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
BACKGROUND: We evaluated topoisomerase I (TOPO1) expression in patients with small cell lung cancer (SCLC) and identified predictive factors for the efficacy of second-line topotecan chemotherapy.
METHODS: We retrospectively evaluated the records of SCLC patients treated in our department from January 2007 to December 2016 who received second-line topotecan chemotherapy. Patients with archived tumor samples were enrolled. TOPO1 expression levels were evaluated by immunohistochemistry, and the relationships between TOPO1 expression, clinical factors, chemotherapy efficacy, and survival were analyzed.
RESULTS: Of the 78 patients enrolled, 67 showed TOPO1 expression (85.9%). Patients were divided into strong (n = 43) or weak (n = 35) expression groups based on staining intensity. Disease control rates for topotecan were 39.5% and 14.3% in the strong and weak groups, respectively (P = 0.014). Second-line median progression-free survival was 2.2 and 2.0 months (P = 0.057), and median overall survival was 8.1 and 6.0 months (P = 0.199) in the strong and weak positive groups, respectively. Patients were also divided into sensitive (n = 47) and refractory (n = 31) disease groups according to the duration from the onset of first-line therapy to relapse. Median second-line progression-free survival was 2.2 and 1.8 months in the sensitive and refractory relapse groups, respectively (P = 0.005).
CONCLUSIONS: TOPO1 expression was prevalent in SCLC patients. Strong expression was associated with an elevated disease control rate after second-line topotecan chemotherapy. Patients with sensitive disease that relapsed after first-line chemotherapy had better survival than refractory patients who received second-line topotecan chemotherapy.

Naro Y, Ankenbruck N, Thomas M, et al.
Small Molecule Inhibition of MicroRNA miR-21 Rescues Chemosensitivity of Renal-Cell Carcinoma to Topotecan.
J Med Chem. 2018; 61(14):5900-5909 [PubMed] Related Publications
Chemical probes of microRNA (miRNA) function are potential tools for understanding miRNA biology that also provide new approaches for discovering therapeutics for miRNA-associated diseases. MicroRNA-21 (miR-21) is an oncogenic miRNA that is overexpressed in most cancers and has been strongly associated with driving chemoresistance in cancers such as renal cell carcinoma (RCC). Using a cell-based luciferase reporter assay to screen small molecules, we identified a novel inhibitor of miR-21 function. Following structure-activity relationship studies, an optimized lead compound demonstrated cytotoxicity in several cancer cell lines. In a chemoresistant-RCC cell line, inhibition of miR-21 via small molecule treatment rescued the expression of tumor-suppressor proteins and sensitized cells to topotecan-induced apoptosis. This resulted in a >10-fold improvement in topotecan activity in cell viability and clonogenic assays. Overall, this work reports a novel small molecule inhibitor for perturbing miR-21 function and demonstrates an approach to enhancing the potency of chemotherapeutics specifically for cancers derived from oncomir addiction.

Kuehl PJ, Grimes MJ, Dubose D, et al.
Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model.
Drug Deliv. 2018; 25(1):1127-1136 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (p < .00001). These results indicate that inhalation delivery increases topotecan exposure of lung tissue and improves its efficacy against lung cancer while also lowering the effective dose and maximum systemic concentration that is responsible for its dose-limiting toxicity.

Rao R, Honavar SG, Mulay K, Reddy VAP
Eye salvage in diffuse anterior retinoblastoma using systemic chemotherapy with periocular and intravitreal topotecan.
J AAPOS. 2018; 22(3):235-237.e2 [PubMed] Related Publications
Diffuse anterior retinoblastoma is an infrequent presentation in which the tumor is confined to the anterior segment, and there is no retinal mass. An 18-month-old Asian Indian boy presented with white spots in the left eye. There were extensive anterior segment seeds without a retinal tumor. Fine-needle aspiration biopsy confirmed the diagnosis of retinoblastoma, and the patient received intravenous chemotherapy with a combination of vincristine-carboplatin-etoposide, periocular topotecan, and intravitreal topotecan to achieve complete tumor regression.

Moon JY, Song IC, Ko YB, Lee HJ
The combination of cisplatin and topotecan as a second-line treatment for patients with advanced/recurrent uterine cervix cancer.
Medicine (Baltimore). 2018; 97(14):e0340 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
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.

Du H, Liu Y, Chen X, et al.
DT-13 synergistically potentiates the sensitivity of gastric cancer cells to topotecan via cell cycle arrest in vitro and in vivo.
Eur J Pharmacol. 2018; 818:124-131 [PubMed] Related Publications
Natural medicine has multi-levels, multi-paths and multi-targets, and an increasing number of reports have confirmed that the combination of natural medicine with chemotherapy drugs exhibit a significant synergistic effect. It is necessary to find drug combination strategies to enhance efficacy and reduce toxicity, which can relieve the restrictions on the use of several chemotherapy drugs that have serious toxicity. Our previous reports showed that DT-13 inhibits cancer proliferation, invasion, migration, metastasis, and angiogenesis and induces autophagy. In this study, we evaluated the anti-proliferation effect of DT-13 on a panel of 40 different cancer cell lines for the first time. Moreover, it is also the first time that the combination of DT-13 with 5 different chemotherapy drugs on 3 common cancer cells has been examined. We further confirmed that DT-13 enhanced the sensitivity of gastric cancer cells to topotecan (TPT) via cell cycle arrest in vitro and in vivo. Considering that TPT has been subjected to restriction because of its serious toxicity, DT-13 showed the ability to enhance its effect and reduce its toxicity, which could provide a strategy to reduce the toxic and clinical side effects of TPT.

Rao R, Honavar SG, Sharma V, Reddy VAP
Intravitreal topotecan in the management of refractory and recurrent vitreous seeds in retinoblastoma.
Br J Ophthalmol. 2018; 102(4):490-495 [PubMed] Related Publications
BACKGROUND/AIM: To evaluate the efficacy of intravitreal topotecan for refractory or recurrent vitreous seeds in retinoblastoma.
METHODS: Intravitreal injection of topotecan hydrochloride (30 µg/0.15 mL) was provided every 3 weeks by the safety enhanced technique.
RESULTS: The study included 17 consecutive patients with retinoblastoma with refractory or recurrent vitreous seeds. Five eyes (29%) belonged to International Classification of Retinoblastoma group C and 12 eyes (71%) belonged to group D. Primary treatment included triple drug intravenous chemotherapy for a mean of 10 cycles (median, 9 cycles; range, 6-18 cycles). Fifteen patients (88%) had undergone 56 periocular carboplatin injections with a mean of 4 injections (median, 3 injections; range, 1-8 injections), concurrent with intravenous chemotherapy. A total of 53 intravitreal topotecan injections were performed in 17 eyes of 17 consecutive patients with refractory or recurrent vitreous seeds with a mean of 3 injections (median, 3 injections; range, 2-6 injections). Complete regression of vitreous seeds was achieved in 17 of 17 eyes (100%). At a mean follow-up of 23.8 months (median, 24 months; range, 15.1-34.1 months), one eye (6%) with a recurrent retinal tumour needed enucleation, and the rest of the 16 eyes (94%) maintained complete regression. Final visual acuity could be reliably assessed in all 16 eyes (100%), of whom 12 eyes (75%) had visual acuity ≥20/200. None of the patients developed ocular or systemic complications.
CONCLUSION: Three-weekly intravitreal topotecan appears effective and safe in controlling focal or diffuse refractory or recurrent vitreous seeds in retinoblastoma.

Pascual-Pasto G, Olaciregui NG, Opezzo JAW, et al.
Increased delivery of chemotherapy to the vitreous by inhibition of the blood-retinal barrier.
J Control Release. 2017; 264:34-44 [PubMed] Related Publications
Treatment of retinoblastoma -a pediatric cancer of the developing retina- might benefit from strategies to inhibit the blood-retinal barrier (BRB). The potent anticancer agent topotecan is a substrate of efflux transporters BCRP and P-gp, which are expressed at the BRB to restrict vitreous and retinal distribution of xenobiotics. In this work we have studied vitreous and retinal distribution, tumor accumulation and antitumor activity of topotecan, using pantoprazole as inhibitor of BCRP and P-gp. We used rabbit and mouse eyes as BRB models and patient-derived xenografts as retinoblastoma models. To validate the rabbit BRB model we stained BCRP and P-gp in the retinal vessels. Using intravitreous microdialysis we showed that the penetration of the rabbit vitreous by lactone topotecan increased significantly upon concomitant administration of pantoprazole (P=0.0285). Pantoprazole also increased topotecan penetration of the mouse vitreous, measured as the vitreous-to-plasma topotecan concentration ratio at the steady state (P=0.0246). Pantoprazole increased topotecan antitumor efficacy and intracellular penetration in retinoblastoma in vitro, but did not enhance intratumor drug distribution and survival in mice bearing the intraocular human tumor HSJD-RBT-2. Anatomical differences with the clinical setting likely limited our in vivo study, since xenografts were poorly vascularized masses that loaded most of the vitreous compartment. We conclude that pharmacological modulation of the BRB is feasible, enhances anticancer drug distribution into the vitreous and might have clinical implications in retinoblastoma.
CHEMICAL COMPOUNDS INCLUDED IN THIS MANUSCRIPT: Topotecan (PubChem CID: 60700) Pantoprazole sodium (PubChem CID: 15008962).

Koosha F, Neshasteh-Riz A, Takavar A, et al.
The combination of A-966492 and Topotecan for effective radiosensitization on glioblastoma spheroids.
Biochem Biophys Res Commun. 2017; 491(4):1092-1097 [PubMed] Related Publications
Radiotherapy is one of the modalities in the treatment of glioblastoma patients, but glioma tumors are resistant to radiation and also chemotherapy drugs. Thus, researchers are investigating drugs which have radiosensitization capabilities in order to improve radiotherapy. PARP enzymes and topoisomerase I enzymes have a critical role in repairing DNA damage in tumor cells. Thus, inhibiting activity of these enzymes helps stop DNA damage repair and increase DSB lethal damages. In the current study, we investigated the combination of TPT as a topoisomerase I inhibitor, and A-966492 as a novel PARP inhibitor for further radiosensitization. U87MG cells (a human glioblastoma cell line) were cultured in Poly-Hema coated flasks to reach 300 μm-diameter spheroids. Treatments were accomplished by using non-toxic concentrations of A-966492 and Topotecan. The surviving fraction of treated cells was determined by clonogenic assay after treatment with drugs and 6 MV X-ray. The γ-H2AX expression was measured by an immunofluorescence staining method to examine the influence of A-966492, TPT and radiation on the induction of double stranded DNA breaks. Treatments using the A-966492 drug were conducted in concentration of 1 μM. Combining A-966492 and TPT with radiation yielded enhanced cell killing, as demonstrated by a sensitizer enhancement ratio at 50% survival (SER

Bernstock JD, Ye D, Gessler FA, et al.
Topotecan is a potent inhibitor of SUMOylation in glioblastoma multiforme and alters both cellular replication and metabolic programming.
Sci Rep. 2017; 7(1):7425 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Protein SUMOylation is a dynamic post-translational modification shown to be involved in a diverse set of physiologic processes throughout the cell. SUMOylation has also been shown to play a role in the pathobiology of myriad cancers, one of which is glioblastoma multiforme (GBM). As such, the clinical significance and therapeutic utility offered via the selective control of global SUMOylation is readily apparent. There are, however, relatively few known/effective inhibitors of global SUMO-conjugation. Herein we describe the identification of topotecan as a novel inhibitor of global SUMOylation. We also provide evidence that inhibition of SUMOylation by topotecan is associated with reduced levels of CDK6 and HIF-1α, as well as pronounced changes in cell cycle progression and cellular metabolism, thereby highlighting its putative role as an adjuvant therapy in defined GBM patient populations.

Chernov L, Deyell RJ, Anantha M, et al.
Optimization of liposomal topotecan for use in treating neuroblastoma.
Cancer Med. 2017; 6(6):1240-1254 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
The purpose of this work was to develop an optimized liposomal formulation of topotecan for use in the treatment of patients with neuroblastoma. Drug exposure time studies were used to determine that topotecan (Hycamtin) exhibited great cytotoxic activity against SK-N-SH, IMR-32 and LAN-1 neuroblastoma human cell lines. Sphingomyelin (SM)/cholesterol (Chol) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/Chol liposomes were prepared using extrusion methods and then loaded with topotecan by pH gradient and copper-drug complexation. In vitro studies showed that SM/Chol liposomes retained topotecan significantly better than DSPC/Chol liposomes. Decreasing the drug-to-lipid ratio engendered significant increases in drug retention. Dose-range finding studies on NRG mice indicated that an optimized SM/Chol liposomal formulation of topotecan prepared with a final drug-to-lipid ratio of 0.025 (mol: mol) was better tolerated than the previously described DSPC/Chol topotecan formulation. Pharmacokinetic studies showed that the optimized SM/Chol liposomal topotecan exhibited a 10-fold increase in plasma half-life and a 1000-fold increase in AUC

Rishi P, Sharma T, Sharma M, et al.
Intra-arterial chemotherapy for retinoblastoma: Two-year results from tertiary eye-care center in India.
Indian J Ophthalmol. 2017; 65(4):311-315 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
AIM: The aim of this study is to describe treatment outcomes and complications of selective intra-arterial chemotherapy (IAC) for intraocular retinoblastoma (RB).
MATERIALS AND METHODS: A retrospective, interventional series of 10 eyes with RB which underwent IAC using melphalan (5 mg/7.5 mg) and topotecan (1 mg), or melphalan (5 mg/7.5 mg) alone. Treatment outcomes were evaluated in terms of tumor control, vitreous seeds (VS) and subretinal seeds (SRS) control, and globe salvage rates.
RESULTS: Ten eyes of 10 patients underwent 38 IAC sessions (mean = 3.8; median = 4; range = 3-5 sessions). Following IAC, complete regression of main tumor was seen in 9 eyes (90%) and partial regression in 1 (10%). All four eyes with SRS showed complete regression (100%). Of 5 eyes with VS, 3 eyes (60%) showed complete regression, 1 eye (20%) showed relapse, while 1 eye (20%) showed no response. Globe salvage was achieved in 8 of 10 eyes (80%). Complications included transient ophthalmic artery narrowing (n = 2), branched retinal vein occlusion (n = 1), forehead skin pigmentation (n = 1), and vitreous hemorrhage (n = 2). There was no case of stroke, hemiplegia, metastasis, or death. Transient hematological changes included relative pancytopenia (n = 4), relative leukopenia (n = 5), and relative thrombocytopenia (n = 4). Mean follow-up was 26 months (median = 28, range = 13-36) from the initiation of first IAC.
CONCLUSIONS: IAC is an effective therapy for globe preservation in eyes with intraocular RB, in the setting of a developing country like India. Larger studies with longer follow-up are required to validate these results.

Schmidt C, Schubert NA, Brabetz S, et al.
Preclinical drug screen reveals topotecan, actinomycin D, and volasertib as potential new therapeutic candidates for ETMR brain tumor patients.
Neuro Oncol. 2017; 19(12):1607-1617 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background: Embryonal tumor with multilayered rosettes (ETMR) is a rare and aggressive embryonal brain tumor that solely occurs in infants and young children and has only recently been recognized as a separate brain tumor entity in the World Health Organization classification for CNS tumors. Patients have a very dismal prognosis with a median survival of 12 months upon diagnosis despite aggressive treatment. The aim of this study was to develop novel treatment regimens in a preclinical drug screen in order to inform potentially more active clinical trial protocols.
Methods: We have carried out an in vitro and in vivo drug screen using the ETMR cell line BT183 and its xenograft model. Furthermore, we have generated the first patient-derived xenograft (PDX) model for ETMR and evaluated our top drug candidates in an in vitro drug screen using this model.
Results: BT183 cells are very sensitive to the topoisomerase inhibitors topotecan and doxorubicin, to the epigenetic agents decitabine and panobinostat, to actinomycin D, and to targeted drugs such as the polo-like kinase 1 (PLK1) inhibitor volasertib, the aurora kinase A inhibitor alisertib, and the mammalian target of rapamycin (mTOR) inhibitor MLN0128. In xenograft mice, monotherapy with topotecan, volasertib, and actinomycin D led to a temporary response in tumor growth and a significant increase in survival. Finally, using multi-agent treatment regimens of topotecan or doxorubicin combined with methotrexate and vincristine, the response in tumor growth and survival was further increased compared with mice receiving single treatments.
Conclusions: We have identified several promising candidates for combination therapies in future clinical trials for ETMR patients.

Klejewski A, Świerczewska M, Zaorska K, et al.
New and Old Genes Associated with Topotecan Resistance Development in Ovarian Cancer Cell Lines.
Anticancer Res. 2017; 37(4):1625-1636 [PubMed] Related Publications
BACKGROUND: Low effectiveness of chemotherapy in ovarian cancer results from development of drug resistance. Topotecan is a drug used as second-line chemotherapy for this cancer type. We analyzed development of topotecan resistance in ovarian cancer cell lines.
MATERIALS AND METHODS: A chemosensitivity assay, MTT test, was performed to assess drug resistance. Quantitative polymerase chain reaction (Q-PCR) assays were performed to determine ABCB1, ABCG2, ALDH1A1, IFIH1, SAMD4 and EPHA3 gene expression.
RESULTS: We observed dose-dependent responses to topotecan. In all topotecan-resistant cell lines an overexpression of ABCG2, IFIH1 and SAMD4 genes was observed. Expression of ABCB1 gene was observed in one cell line. Expression of ALDH1A1 was up-regulated in A2780 and down-regulated in SKOV-3-resistant cell lines. Short-time exposure led to similar patterns of gene expression for the investigated genes.
CONCLUSION: Expression of ABCG2 and ABCB1 genes plays the most important role in topotecan resistance. The role of other investigated genes seems to be complementary.

Poveda A, Del Campo JM, Ray-Coquard I, et al.
Phase II randomized study of PM01183 versus topotecan in patients with platinum-resistant/refractory advanced ovarian cancer.
Ann Oncol. 2017; 28(6):1280-1287 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
Background: PM01183 is a new compound that blocks active transcription, produces DNA breaks and apoptosis, and affects the inflammatory microenvironment. PM01183 showed strong antitumor activity in preclinical models of cisplatin-resistant epithelial ovarian cancer.
Patients and methods: Patients with platinum-resistant/refractory ovarian cancer were included in a two-stage, controlled, randomized (in a second stage), multicenter, phase II study. Primary endpoint was overall response rate (ORR) by RECIST and/or GCIG criteria. The exploratory first stage (n = 22) confirmed the activity of PM01183 as a single agent at 7.0 mg flat dose every 3 weeks (q3wk). The second stage (n = 59) was randomized and controlled with topotecan on days 1-5 q3wk or weekly (every 4 weeks, q4wk).
Results: ORR was 23% (95% CI, 13%-37%) for 52 PM01183-treated patients. Median duration of response was 4.6 months (95% CI, 2.5-6.9 months), and 23% (95% CI, 0%-51%) of responses lasted 6 months or more. Ten of the 12 confirmed responses were reported for 33 patients with platinum-resistant disease [ORR = 30% (95% CI, 16%-49%)]; for the 29 patients treated with topotecan in the second stage, no responses were found. Median PFS for all PM01183-treated patients was 4.0 months (95% CI, 2.7-5.6 months), and 5.0 months (95% CI, 2.7-6.9 months) for patients with platinum-resistant disease. Grade 3/4 neutropenia in 85% of patients; febrile neutropenia in 21% and fatigue (grade 3 in 35%) were the principal safety findings for PM01183.
Conclusion: PM01183 is an active drug in platinum-resistant/refractory ovarian cancer and warrants further development. The highest activity was observed in platinum-resistant disease. Its safety profile indicates the dose should be adjusted to body surface area (mg/m2).
Trial code: EudraCT 2011-002172-16.

Karl MD, Francis JH, Iyer S, et al.
Intraocular Pressure Changes Following Intravitreal Melphalan and Topotecan for the Treatment of Retinoblastoma With Vitreous Seeding.
J Pediatr Ophthalmol Strabismus. 2017; 54(3):185-190 [PubMed] Article available free on PMC after 01/10/2019 Related Publications
PURPOSE: To investigate the impact of intravitreal chemotherapy on intraocular pressure (IOP) in children with retinoblastoma.
METHODS: This was a retrospective study of 10 eyes of 10 patients with retinoblastoma (7 males, 3 females, mean age: 33.6 ± 9.4 months) with vitreous seeding injected with intravitreal melphalan and topotecan. IOP was measured with Tonopen (Reichert, Inc., Buffalo, NY) at baseline prior to injecting and then repeatedly following each intravitreal injection.
RESULTS: Mean pre-injection IOP was 8.2 ± 2.3 mm Hg (range: 4 to 12 mm Hg). Mean IOP 1 to 30 seconds after intravitreal melphalan (first injection) was 45.4 ± 14.3 mm Hg. The IOP of 89.5% of patients declined to 29 mm Hg or less in a mean 153.3 ± 97.5 seconds. Mean IOP 1 to 30 seconds after intravitreal topotecan (second injection) was 44.5 ± 11.0 mm Hg, which decreased to 31.0 ± 5.0 mm Hg by 150 seconds after injection. No significant relationship was found between age and post-injection IOP elevation. IOP exceeded the calculated mean arterial perfusion pressure in four encounters.
CONCLUSIONS: Intravitreal chemotherapy caused a transient rise in IOP. Post-injection IOP elevations can reach levels that may exceed mean arterial pressure. [J Pediatr Ophthalmol Strabismus. 2017;54(3):185-190.].

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