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Investigative Ophthalmology & Visual... Sep 2023Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term...
PURPOSE
Surgery, multiagent systemic chemotherapy, and radiation are used for patients with orbital retinoblastoma but are associated with unacceptable short- and long-term toxicity (including death). We studied orbital and systemic exposure of topotecan in the swine model after ophthalmic artery chemosurgery (OAC) and intravenous (IV) delivery.
METHODS
Landrace pigs (n = 3) underwent 30-minute OAC of topotecan (4 mg), and samples were serially obtained from the femoral artery and from a microdialysis probe inserted into the lateral rectus muscle sheath of the infused eye as a surrogate of the orbital irrigation. Animals were recovered, and, after a wash-out period, plasma and microdialysate samples from the contralateral eye were collected after a 30-minute IV infusion of topotecan (4 mg). Samples were quantified by high-performance liquid chromatography, and population pharmacokinetic analysis was conducted using MonolixSuite.
RESULTS
After OAC, median topotecan exposure in the orbit was 5624 ng × h/mL (range 3922-12531) compared to 23 ng × h/mL (range 18-75) after IV infusion. Thus, topotecan exposure in the orbit was 218-fold (range 75-540) higher after OAC than after IV infusion despite comparable systemic exposure (AUCpl) between routes (AUCpl, OAC: 141 ng × h/mL [127-191] versus AUCpl, IV: 139 ng × h/mL [126-186]). OAC was more selective to target the orbit because the median (range) orbital-to-plasma exposure ratio was 44 (28-65) after OAC compared to 0.18 (0.13-0.40) after IV infusion.
CONCLUSIONS
OAC of topotecan resulted in higher orbital exposure than after IV infusion and was a more selective route for local drug delivery. Patients with orbital retinoblastoma may benefit from a multimodal treatment strategy including OAC therapy.
Topics: Animals; Swine; Infusions, Intravenous; Ophthalmic Artery; Topotecan; Retinoblastoma; Retinal Neoplasms
PubMed: 37656475
DOI: 10.1167/iovs.64.12.3 -
The Oncologist 2004Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early regional and distant metastasis. Response rates to first-line chemotherapy are... (Review)
Review
Small cell lung cancer (SCLC) is an aggressive malignancy with a high propensity for early regional and distant metastasis. Response rates to first-line chemotherapy are typically high, but short lived. The outlook for patients with recurrent SCLC is poor. A variety of single- and multi-agent chemotherapy regimens have met with limited success in patients with recurrent SCLC, and survival is generally measured in weeks. Until recently, further chemotherapy was not widely considered appropriate for patients with relapsed SCLC. The choice of chemotherapy at relapse is dependent on many factors, including type of and response to first-line therapy, the treatment-free interval, and the patient's performance status. Intravenous topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA) has provided oncologists and patients in many countries with an effective and tolerable therapeutic option for recurrent SCLC. The clinical profile of topotecan was established in several phase II studies and confirmed in a randomized, phase III trial versus cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH), and vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN)--CAV. In those studies, topotecan exhibited antitumor activity in both chemosensitive and refractory disease. Further, topotecan therapy is associated with significant symptom palliation in this patient population. Because the toxicity profile of topotecan is predictable, generally manageable, and noncumulative, the agent also has potential utility in patients with a poor prognosis and/or a poor performance status. Alternative dosing regimens (lower dose, weekly) and the introduction of an oral formulation may expand the use of topotecan as a single agent and in combination therapy in the second- and first-line treatment of this disease.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Topotecan
PubMed: 15616145
DOI: 10.1634/theoncologist.9-90006-4 -
The Oncologist Oct 2005The purpose was to conduct an integrated analysis of the cumulative hematologic toxicity of topotecan in patients with relapsed ovarian cancer and small cell lung cancer... (Review)
Review
The purpose was to conduct an integrated analysis of the cumulative hematologic toxicity of topotecan in patients with relapsed ovarian cancer and small cell lung cancer (SCLC). Data were pooled from eight phase II and phase III clinical studies performed in patients with relapsed stage III/IV ovarian cancer or extensive SCLC treated with topotecan at a dose of 1.5 mg/m(2) per day on days 1-5 of a 21-day course. Quantitative hematologic toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. A total of 4,124 courses of therapy was administered to the 879 patients in the pooled population. Grade 4 neutropenia was experienced by 78% of patients. The lowest nadirs for neutrophils and platelets generally occurred after the first course of therapy, followed by improvement or stabilization in subsequent courses. Neutropenia was noncumulative. During the first course, significant risk factors were identified: renal impairment and advanced age (grade 3/4 thrombocytopenia and grade 4 neutropenia) and prior radiotherapy; performance status score > or =2; SCLC; and exposure to both cisplatin (Platinol; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and carboplatin (Paraplatin; Bristol-Myers Squibb) (grade 3/4 thrombocytopenia only). The most frequent interventions for hematologic toxicities were RBC transfusions, treatment delays, G-CSF support, and dose reductions. Analysis of neutrophil and platelet nadirs and dosing for each course of therapy showed no apparent evidence of cumulative neutropenia or thrombocytopenia. The risk of grade 3 or 4 anemia was higher during the first four courses of therapy and may need to be more aggressively managed with erythropoietin therapy.
Topics: Antineoplastic Agents; Bone Marrow; Carcinoma, Small Cell; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Hemoglobins; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Ovarian Neoplasms; Topotecan
PubMed: 16249347
DOI: 10.1634/theoncologist.10-9-686 -
Journal of Cancer Research and... 2018Glioblastoma multiform (GBM) is one of the most common brain tumors. Surgery, radiation therapy, hyperthermia, and chemotherapy are the most common treatments for brain...
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.
Topics: Brain Neoplasms; Cell Survival; DNA Damage; Fever; Glioblastoma; Humans; Spheroids, Cellular; Topoisomerase I Inhibitors; Topotecan; Tumor Cells, Cultured; X-Rays
PubMed: 30488843
DOI: 10.4103/0973-1482.189239 -
Annals of Oncology : Official Journal... Sep 1997This review presents a summary of preclinical and clinical data on the topoisomerase I (topo I) inhibitors that are under clinical development. To date, all of the topo... (Review)
Review
This review presents a summary of preclinical and clinical data on the topoisomerase I (topo I) inhibitors that are under clinical development. To date, all of the topo I inhibitors that have been clinically evaluated are analogues of camptothecin, an extract of the Chinese tree Camptotheca acuminata. The therapeutic development of camptothecin was initially limited by its poor solubility and unpredictable toxicity. More recently, a number of water-soluble camptothecin analogues have undergone extensive evaluation and have demonstrated significant clinical activity. These include irinotecan (CPT-II), topotecan, and 9-aminocamptothecin (9-AC). Preliminary data are also reviewed on other camptothecin analogues (GG-211 and DX-8951f), on oral formulations, and on non-camptothecin topoisomerase I inhibitors. The topoisomerase I inhibitors have already demonstrated a broad spectrum of antitumour activity, most probably due to their unique mechanism of action and lack of clinical cross-resistance with existing antineoplastic compounds. The challenge for the next five years is to identify ways to integrate the topo I inhibitors into multidrug and multimodality therapies to achieve optimal antitumour effect, while keeping the side effects of these therapies manageable.
Topics: Animals; Antineoplastic Agents; Camptothecin; Clinical Trials as Topic; Drug Resistance, Neoplasm; Enzyme Inhibitors; Humans; Irinotecan; Topoisomerase I Inhibitors; Topotecan
PubMed: 9358934
DOI: 10.1023/a:1008270717294 -
International Journal of Gynecological... 2005The response to salvage treatment in recurrent epithelial ovarian cancer (REOC), is influenced by many biologic features which should be taken into account in the... (Review)
Review
The response to salvage treatment in recurrent epithelial ovarian cancer (REOC), is influenced by many biologic features which should be taken into account in the process of therapeutic decision. Until recently, single agents have been considered effective as combination chemotherapy in REOC and they still represent an option for well-defined categories of patients. In clinical practice, the selection of drugs for second-line treatment can be based on the knowledge that tumor size and response to prior platinum are predictors of response and that the efficacy of some commonly used single agents is supported by well designed clinical studies. Only two single-agent randomized studies with long-term survival analyses have been published; in the topotecan versus paclitaxel study, performed on a total of 235 patients, the long-term survival results did not confirm the initial report of a superiority of topotecan, with a median survival of 63 weeks and 53 weeks for patients treated with topotecan, and, respectively, paclitaxel. No comparative data were provided in the subgroup of potentially platinum-sensitive disease. In the phase III study of pegylated liposomal doxorubicin versus topotecan, into which 474 patients were treated between 1997 and 1999, the higher efficacy of pegylated liposomal doxorubicin was even more evident in the long-term survival analysis, with a 18% reduction in the risk of death, in the overall population which increased to 30% in the subset of platinum-sensitive patients. The survival after the two treatments, however, was not different in the group of patients with platinum-refractory disease. The toxicity profile of the two drugs was completely different, with palmar-plantar erythrodysestesia as most common adverse event after pegylated doxo (35% of patients) and severe neutropenia after topotecan (77% of patients). These data confirm the role of pegylated liposomal doxorubicin in the management of REOC and indicate that the identification of new active drugs in this disease is relevant but also feasible only in platinum-sensitive patients.
Topics: Antineoplastic Agents; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Neoplasm Recurrence, Local; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Paclitaxel; Polyethylene Glycols; Randomized Controlled Trials as Topic; Survival Analysis; Topotecan
PubMed: 16343240
DOI: 10.1111/j.1525-1438.2005.00437.x -
Cell Reports Aug 2023The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but...
The neddylation inhibitor MLN4924/Pevonedistat is in clinical trials for multiple cancers. Efficacy is generally attributed to cullin RING ligase (CRL) inhibition, but the contribution of non-CRL targets is unknown. Here, CRISPR screens map MLN4924-monotherapy sensitivity in retinoblastoma to a classic DNA damage-induced p53/E2F3/BAX-dependent death effector network, which synergizes with Nutlin3a or Navitoclax. In monotherapy-resistant cells, MLN4924 plus standard-of-care topotecan overcomes resistance, but reduces DNA damage, instead harnessing ribosomal protein nucleolar-expulsion to engage an RPL11/p21/MYCN/E2F3/p53/BAX synergy network that exhibits extensive cross-regulation. Strikingly, unneddylatable RPL11 substitutes for MLN4924 to perturb nucleolar function and enhance topotecan efficacy. Orthotopic tumors exhibit complete responses while preserving visual function. Moreover, MLN4924 plus melphalan deploy this DNA damage-independent strategy to synergistically kill multiple myeloma cells. Thus, MLN4924 synergizes with standard-of-care drugs to unlock a nucleolar death effector network across cancer types implying broad therapeutic relevance.
Topics: Topotecan; Tumor Suppressor Protein p53; bcl-2-Associated X Protein; Cell Line, Tumor; Cyclopentanes; Ribosomal Proteins; Apoptosis; NEDD8 Protein
PubMed: 37552601
DOI: 10.1016/j.celrep.2023.112925 -
Health Technology Assessment... Mar 2006To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH)... (Review)
Review
Topotecan, pegylated liposomal doxorubicin hydrochloride and paclitaxel for second-line or subsequent treatment of advanced ovarian cancer: a systematic review and economic evaluation.
OBJECTIVES
To examine the clinical effectiveness and cost-effectiveness of intravenous formulations of topotecan monotherapy, pegylated liposomal doxorubicin hydorocholoride (PLDH) monotherapy and paclitaxel used alone or in combination with a platinum-based compound for the second-line or subsequent treatment of advanced ovarian cancer.
DATA SOURCES
Electronic databases covering publication years 2000-4. Company submissions.
REVIEW METHODS
Seventeen databases were searched for randomised controlled trials (RCTs) and systematic reviews for the clinical effectiveness of PLDH, topotecan and paclitaxel and economic evaluations of the cost-effectiveness of PLDH, topotecan and paclitaxel. Selected studies were quality assessed and data extracted, as were the three company submissions. A new model was developed to assess the costs of the alternative treatments, the differential mean survival duration and the impact of health-related quality of life. Monte-Carlo simulation was used to reflect uncertainty in the cost-effectiveness results.
RESULTS
Nine RCTs were identified. In five of these trials, both the comparators were used within their licensed indications. Of these five, three included participants with both platinum-resistant and platinum-sensitive advanced ovarian cancer, and a further two only included participants with platinum-sensitive disease. The comparators that were assessed in the three trials that included both subtypes of participants were PLDH versus topotecan, topotecan versus paclitaxel and PLDH versus paclitaxel. In the further two trials that included participants with the subtype of platinum-sensitive disease, the comparators that were assessed were single-agent paclitaxel versus a combination of cyclophosphamide, doxorubicin and cisplatin (CAP) and paclitaxel plus platinum-based chemotherapy versus conventional platinum-based therapy alone. A further four trials were identified and included in the review in which one of the comparators in the trial was used outside its licensed indication. The comparators assessed in these trials were oxaliplatin versus paclitaxel, paclitaxel given weekly versus every 3 weeks, paclitaxel at two different dose levels and oral versus intravenous topotecan. Four studies met the inclusion criteria for the cost-effectiveness review. The review of the economic evidence from the literature and industry submissions identified a number of significant limitations in existing studies assessing the cost-effectiveness of PLDH, topotecan and paclitaxel. Analysis 1 assessed the cost-effectiveness of PLDH, topotecan and paclitaxel administered as monotherapies. Sensitivity analysis was undertaken to explore the impact of patient heterogeneity (e.g. platinum-sensitive and platinum-resistant/refractory patients), the inclusion of additional trial data and alternative assumptions regarding treatment and monitoring costs. In the base-case results for Analysis 1, paclitaxel monotherapy emerged as the cheapest treatment. When the incremental cost-effectiveness ratios (ICERs) were estimated, topotecan was dominated by PLDH. Hence the options considered in the estimation of the ICERs were paclitaxel and PLDH. The ICER for PLDH compared with paclitaxel was pound 7033 per quality-adjusted life-year (QALY) in the overall patient population (comprising platinum-sensitive, -refractory and -resistant patients). The ICER was more favourable in the platinum-sensitive group ( pound 5777 per QALY) and less favourable in the platinum-refractory/resistant group ( pound 9555 per QALY). The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of the additional trial data resulted in less favourable estimates for the ICER for PLDH versus paclitaxel compared with the base-case results. The ICER of PLDH compared with paclitaxel was pound 20,620 per QALY in the overall patient population, pound 16,183 per QALY in the platinum-sensitive population and pound 26,867 per QALY in the platinum-resistant and -refractory population. The results from Analysis 2 explored the cost-effectiveness of the full range of treatment comparators for platinum-sensitive patients. The treatment options considered in this model comprised PLDH, topotecan, paclitaxel-monotherapy, CAP, paclitaxel/platinum combination therapy and platinum monotherapy. Owing to the less robust approaches that were employed to synthesise the available evidence and the heterogeneity between the different trials, the reliability of these results should be interpreted with some caution. Topotecan, paclitaxel monotherapy and PLDH were all dominated by platinum monotherapy (i.e. higher costs and lower QALYs). After excluding these alternatives, the treatments that remained under consideration were platinum monotherapy, CAP and paclitaxel-platinum combination therapy. Of these three alternatives, platinum monotherapy was the least costly and least effective. The ICER for CAP compared with platinum monotherapy was pound 16,421 per QALY. The ICER for paclitaxel-platinum combination therapy compared with CAP was pound 20,950 per QALY.
CONCLUSIONS
For participants with platinum-resistant disease there was a low probability of response to treatment with PLDH, topotecan or paclitaxel. Furthermore, there was little difference between the three comparators in relation to overall survival. The comparators did, however, differ considerably in their toxicity profiles. Given the low survival times and response rates, it appears that the maintenance of quality of life and the control of symptoms and toxicity are paramount in this patient group. As the three comparators differed significantly in terms of their toxicity profiles, patient and physician choice is also an important element that should be addressed when decisions are made regarding second-line therapy. It can also be suggested that this group of patients may benefit from being included in further clinical trials of new drugs. For participants with platinum-sensitive disease there was a considerable range of median survival times observed across the trials. The most favourable survival times and response rates were observed for paclitaxel and platinum combination therapy. This suggests that treatment with combination therapy may be more beneficial than treatment with a single-agent chemotherapeutic regimen. In terms of single-agent compounds, the evidence suggests that PLDH is more effective than topotecan. Evidence from a further trial that compared PLDH and paclitaxel suggests that there is no significant difference between these two comparators in this trial. The three comparators did, however, differ significantly in terms of their toxicity profiles across the trials. Although treatment with PLDH may therefore be more beneficial than that with topotecan, patient and physician choice as to the potential toxicities associated with each of the comparators and the patient's ability and willingness to tolerate these are of importance. Assuming the NHS is willing to pay up to pound 20,000-40,000 per additional QALY, PLDH appears to be cost-effective compared with topotecan and paclitaxel monotherapy, in terms of the overall patient population and the main subgroups considered. The cost-effectiveness results for the base-case analysis were sensitive to the inclusion of additional trial data. Incorporating the results of additional trial data gave less favourable estimates for the ICER for PLDH versus paclitaxel monotherapy, compared with the base-case results. Although the ICER of PLDH compared with paclitaxel monotherapy was less favourable, PLDH was still cost-effective compared with topotecan and paclitaxel monotherapy. For platinum-sensitive patients, the combination of paclitaxel and platinum appears to be cost-effective. On the strength of the evidence reviewed here, it can be suggested that participants with platinum-resistant disease may benefit from being included in further clinical trials of new drugs. To assess the effectiveness of combination therapy against a single-agent non-platinum-based compound, it can be suggested that a trial that compared paclitaxel in combination with a platinum-based therapy versus single-agent PLDH would be a reasonable option.
Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Cost-Benefit Analysis; Doxorubicin; Female; Humans; Liposomes; Ovarian Neoplasms; Paclitaxel; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis; Topotecan
PubMed: 16545208
DOI: 10.3310/hta10090 -
Biochimica Et Biophysica Acta.... Dec 2022SUMO-specific proteases (SENPs) play pivotal roles in maintaining the balance of SUMOylation/de-SUMOylation and in SUMO recycling. Deregulation of SENPs leads to...
SUMO-specific proteases (SENPs) play pivotal roles in maintaining the balance of SUMOylation/de-SUMOylation and in SUMO recycling. Deregulation of SENPs leads to cellular dysfunction and corresponding diseases. As a key member of the SENP family, SENP1 is highly correlated with various cancers. However, the potential role of SENP1 in leukemia, especially in acute lymphoblastic leukemia (ALL), is not clear. This study shows that ALL cells knocking down SENP1 display compromised growth rather than significant alterations in chemosensitivity, although ALL relapse samples have a relatively higher expression of SENP1 than the paired diagnosis samples. Camptothecin derivatives 7-ethylcamptothecin (7E-CPT, a monomer compound) and topotecan (TPT, an approved clinical drug) induce specific SENP1 reduction and severe apoptosis of ALL cells, showing strong anticancer effects against ALL. Conversely, SENP1 could attenuate this inhibitory effect by targeting DNA topoisomerase I (TOP1) for de-SUMOylation, indicating that specific reduction in SENP1 induced by 7E-CPT and/or topotecan inhibits the proliferation of ALL cells.
Topics: Cysteine Endopeptidases; DNA Topoisomerases, Type I; Sumoylation; Topoisomerase I Inhibitors; Topotecan
PubMed: 35850175
DOI: 10.1016/j.bbadis.2022.166492 -
Cancer Research Communications Aug 2023Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an model of human solid tumors to investigate the...
UNLABELLED
Multicellular spheroids comprised of malignant cells, endothelial cells, and mesenchymal stem cells served as an model of human solid tumors to investigate the potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways. The DNA-damaging drugs, topotecan, trabectedin, and temozolomide were combined with varied inhibitors of DNA damage response enzymes including PARP (olaparib or talazoparib), ATM (ataxia telangiectasia mutated; AZD-1390), ATR (ataxia telangiectasia and Rad3-related protein; berzosertib or elimusertib), and DNA-PK (DNA-dependent protein kinase; nedisertib or VX-984). A range of clinically achievable concentrations were tested up to the clinical , if known. Mechanistically, the types of DNA damage induced by temozolomide, topotecan, and trabectedin are distinct, which was apparent from the response of spheroids to combinations with various DNA repair inhibitors. Although most combinations resulted in additive cytotoxicity, synergistic activity was observed for temozolomide combined with PARP inhibitors as well as combinations of the ATM inhibitor AZD-1390 with either topotecan or trabectedin. These findings might provide guidance for the selection of anticancer agent combinations worthy of further investigation.
SIGNIFICANCE
Clinical efficacy of DNA-damaging anticancer drugs can be influenced by the DNA damage response in tumor cells. The potentiation of DNA-damaging drugs by pharmacologic modulation of DNA repair pathways was assessed in multicellular tumor spheroids. Although most combinations demonstrated additive cytotoxicity, synergistic cytotoxicity was observed for several drug combinations.
Topics: Humans; Temozolomide; Trabectedin; Ataxia Telangiectasia; Endothelial Cells; Spheroids, Cellular; Topotecan; Neoplasms; DNA Repair; DNA; DNA-Activated Protein Kinase
PubMed: 37637936
DOI: 10.1158/2767-9764.CRC-23-0193