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Medicinal Research Reviews Jan 2015Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory... (Review)
Review
Podophyllotoxin (PPT), as well as its congeners and derivatives, exhibits pronounced biological activities, especially antineoplastic effects. Its strong inhibitory effect on tumor cell growth led to the development of three of the most highly prescribed anticancer drugs in the world, etoposide, teniposide, and the water-soluble prodrug etoposide phosphate. Their clinical success as well as intriguing mechanism of action stimulated great interest in further modification of PPT for better antitumor activity. The C-4 position has been a major target for structural derivatization aimed at either producing more potent compounds or overcoming drug resistance. Accordingly, numerous PPT derivatives have been prepared via hemisynthesis and important structure-activity relationship (SAR) correlations have been identified. Several resulting compounds, including GL-331, TOP-53, and NK611, reached clinical trials. Some excellent reviews on the distribution, sources, applications, synthesis, and SAR of PPT have been published. This review focuses on a second generation of new etoposide-related drugs and provides detailed coverage of the current status and recent development of C-4-modified PPT analogs as anticancer clinical trial candidates.
Topics: Animals; Antineoplastic Agents; Humans; Podophyllotoxin; Structure-Activity Relationship
PubMed: 24827545
DOI: 10.1002/med.21319 -
Nanoscale Nov 2015Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide,...
Etoposide phosphate (EP), a water-soluble anticancer prodrug, is widely used for treatment of many cancers. After administration it is rapidly converted to etoposide, its parent compound, which exhibits anticancer activity. Difficulty in parenteral administration necessitates the development of a suitable nanoparticle delivery system for EP. Here we have used indium both as a carrier to deliver etoposide phosphate to tumor cells and as a SPECT imaging agent through incorporation of (111)In. Etoposide phosphate was successfully encapsulated together with indium in nanoparticles, and exhibited dose dependent cytotoxicity and induction of apoptosis in cultured H460 cancer cells via G2/M cell cycle arrest. In a mouse xenograft lung cancer model, etoposide phosphate/indium nanoparticles induce tumor cell apoptosis, leading to significant enhancement of tumor growth inhibition compared to the free drug.
Topics: Animals; Carcinoma, Non-Small-Cell Lung; Drug Carriers; Etoposide; G2 Phase Cell Cycle Checkpoints; Humans; Indium; Lung Neoplasms; M Phase Cell Cycle Checkpoints; Mice; Mice, Nude; Nanoparticles; Organophosphorus Compounds; Theranostic Nanomedicine; Xenograft Model Antitumor Assays
PubMed: 26489694
DOI: 10.1039/c5nr04509f -
Cancer Treatment and Research... 2020Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We...
BACKGROUND
Etoposide phosphate (VP-16) is a topoisomerase 2 (TOP2) inhibitor that demonstrated activity in patients with metastatic castration-resistant prostate cancer (mCRPC). We investigated the sensitivity of prostate cancer (PCa) cells (LNCaP, 22Rv1, PC3, DU145, PDB and MDB) to VP-16 and the possible relationship between VP-16 activity and TOP2 expression. The activity of VP-16 was compared with that of docetaxel, enzalutamide and olaparib. The prevalence and clinical significance of TOP2 genetic and transcriptomic alterations was also explored in mCRPC.
METHODS
Cell cultures and crystal violet cell proliferation assays were performed. Specific antibodies were used in western blots analyses of cell protein extracts. Datasets were analyzed in cBioportal.
RESULTS
VP-16 was active in all PCa cell lines analyzed and demonstrated increased activity in PC3 and DU145 cells. VP-16 was more cytotoxic compared to the other treatments, except for LNCaP and 22Rv1, which were more sensitive to docetaxel. Maintenance of antiandrogen treatment in MDB and PDB increased sensitivity to VP-16, docetaxel and enzalutamide. TOP2A was found overexpressed in 22Rv1, DU145 and PC3, whereas TOP2B was overexpressed in 22Rv1 and PDB. In the mCRPC datasets analysis, TOP2A mRNA overexpression was associated with worse patients' prognosis, with the molecular features of neuroendocrine prostate cancer (NEPC) and with lower androgen receptor (AR) score. Patients overexpressing TOP2A mRNA were more likely to harbor RB1 loss.
CONCLUSIONS
Specific subpopulations of patients with aggressive variant prostate cancer (AVPC) could benefit from VP-16 treatment. TOP2A overexpression, rather than TOP2B, might be a good biomarker to predict response to VP-16.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cell Proliferation; Etoposide; Humans; Male; Organophosphorus Compounds; Prostatic Neoplasms, Castration-Resistant; Topoisomerase II Inhibitors
PubMed: 33091733
DOI: 10.1016/j.ctarc.2020.100221 -
British Journal of Cancer 1997Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic...
Etoposide phosphate is a water-soluble prodrug of etoposide. It was expected that this prodrug could be used to overcome the solubility limitations and erratic bioavailability of oral etoposide. To investigate the possibility of prodrug conversion to etoposide within the gastrointestinal lumen, etoposide phosphate was dissolved in water and incubated with human gastric juice or human bile in vitro. Samples were collected during 150 min and analysed for etoposide concentration with high-performance liquid chromatography. Conversion of prodrug to etoposide during incubation with gastric juice was negligible. There was significant conversion during incubation with bile at pH 7-8. The percentage of prodrug converted to etoposide at pH 8 after 60 min was 78 +/- 18% (mean +/- S.D.) for a 0.1 mg ml-1 prodrug solution and 36 +/- 26% for 0.5 mg ml-1. At pH 7, after 60 min 22% of prodrug was converted to etoposide when incubated at 0.1 mg ml-1 and 10% at 0.5 mg ml-1. No conversion was found after inactivation of alkaline phosphate (AP) by overnight heating of bile at 65 degrees C or by the addition of disodium edetate to the bile. In conclusion, because of AP in bile, variable conversion of etoposide phosphate to etoposide can be expected within the intestinal lumen after oral administration. This could have important pharmacokinetic consequences.
Topics: Antineoplastic Agents, Phytogenic; Bile; Biotransformation; Etoposide; Gastric Juice; Humans; In Vitro Techniques; Organophosphorus Compounds; Prodrugs
PubMed: 9400945
DOI: 10.1038/bjc.1997.581 -
British Journal of Cancer 1997Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Etoposide phosphate is a water-soluble prodrug of etoposide. The plasma pharmacokinetics of etoposide following oral administration of etoposide phosphate or oral etoposide were compared. Seventeen patients with solid tumours were enrolled to receive oral etoposide phosphate 125 mg m(-2) on days 1-5 every 3 weeks, with escalation to 175 mg m(-2) from course 3 when possible. Patients were randomized to receive oral etoposide phosphate or oral etoposide on day 1 of course 1 and the alternative compound on day 1 of course 2. Fifteen patients received two or more courses and were evaluable for pharmacokinetic comparisons. The median AUC(inf) (area under the concentration vs time curve from zero to infinity) of etoposide was 77.7 mg l(-1) h after etoposide phosphate (95% CI 61.3-100.5) and 62.0 mg l(-1) h after oral etoposide (95% CI 52.2-76.9). The difference in favour of etoposide phosphate was borderline significant: median 9.9 mg l(-1) h (95% CI 0.1-32.8 mg l(-1) h; P = 0.05). However, the inter-patient variability of etoposide AUC(inf) was not improved (coefficients of variation 42.3% and 48.4%). Etoposide phosphate was undetectable in plasma after oral administration. Toxicities of oral etoposide phosphate were not different from those known for etoposide. In conclusion, oral etoposide phosphate does not offer a clinically relevant benefit over oral etoposide.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Agents, Phytogenic; Etoposide; Female; Humans; Male; Middle Aged
PubMed: 9184183
DOI: 10.1038/bjc.1997.282 -
European Journal of Hospital Pharmacy :... Sep 2022Risk management for workers involved in the handling and preparation of cytotoxic drugs is challenging. This study aims to investigate drug contamination of the exterior...
Risk management for workers involved in the handling and preparation of cytotoxic drugs is challenging. This study aims to investigate drug contamination of the exterior surfaces of cytotoxic drug vials. Two batches of commercially available cytotoxic drugs in unprotected vials (ifosfamide, etoposide phosphate and cyclophosphamide) and plastic shrink wrap vials (doxorubicin, cytarabine and busulfan) were tested without removing the flip-off cap or the plastic wrap, and without prewashing. The results showed significant trace amounts of cytotoxic drugs on the exterior surfaces in both unprotected (eg, cyclophosphamide, ifosfamide) and protected plastic shrink wrap vials (eg, cytarabine), indicating that the secondary packaging of protected vials does not systematically prevent exposure to the handlers. These results focus on the need for guidelines to prevent cytotoxic vial contamination and safety recommendations for staff in the handling and storage of these vials.
Topics: Antineoplastic Agents; Cyclophosphamide; Cytarabine; Drug Contamination; Drug Packaging; Environmental Monitoring; Humans; Ifosfamide; Occupational Exposure; Plastics
PubMed: 32978219
DOI: 10.1136/ejhpharm-2020-002440 -
European Journal of Hospital Pharmacy :... Jan 2020According to the manufacturers, the diluted solution of etoposide should not exceed 0.4 mg/mL because precipitation may occur. For high doses or for patients requiring...
INTRODUCTION
According to the manufacturers, the diluted solution of etoposide should not exceed 0.4 mg/mL because precipitation may occur. For high doses or for patients requiring fluid restrictions, etoposide phosphate may be an option but shortages occurs frequently. The objective of this work was to study the stability of etoposide solutions between 0.38 and 1.75 mg/mL, diluted in 0.9% sodium chloride (0.9% NaCl) or 5% glucose (G5%) in polyolefin bags, stored at 25°C and between 2°C to 8°C, in a 61-day period. This study also observed the impact of an infusion pump on the physical and chemical stability of etoposide solutions.
MATERIALS AND METHOD
Chemical stability was analysed at days 0, 9, 16, 21, 28 and 61 by high-performance liquid chromatography. Physical stability was evaluated by visual and subvisual inspection. The action of an infusion pump on solutions was evaluated to verify the impact of the mechanical pumping action on the etoposide solutions. This investigation was performed at day 61, at the end of the study.
RESULTS
Etoposide solutions diluted at 0.38, 0.74 and 1.26 mg/mL in G5% and stored at 25°C were stable for 61 days and at 1.75 mg/mL for 28 days. In 0.9% NaCl, etoposide was less stable, with more precipitations observed. The action of an infusion pump has not caused any physical modifications.
CONCLUSION
Storage at 25°C and G5% as diluent are recommended for etoposide high concentration with 61-day stability up to a concentration of 1.26 mg/mL and 28-day stability up to a concentration of 1.75 mg/mL. As a precaution, the use of an administration set with an in-line micro-filter is nevertheless recommended. Storage at 2°C to 8°C and the use of 0.9% NaCl increase the risk of precipitation.
Topics: Chemical Phenomena; Chromatography, High Pressure Liquid; Drug Compounding; Drug Packaging; Drug Stability; Drug Storage; Etoposide; Humans; Pharmaceutical Solutions; Polyenes
PubMed: 32064088
DOI: 10.1136/ejhpharm-2018-001571 -
PloS One 2017Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the...
Comparative oncology has shown that naturally occurring canine cancers are of valuable and translatable interest for the understanding of human cancer biology and the characterization of new therapies. This work was part of a comparative oncology project assessing a new, clinical-stage topoisomerase II inhibitor and comparing it with etoposide in dogs with spontaneous lymphoma with the objective to translate findings from dogs to humans. Etoposide is a topoisomerase II inhibitor widely used in various humans' solid and hematopoietic cancer, but little data is available concerning its potential antitumor efficacy in dogs. Etoposide phosphate is a water-soluble prodrug of etoposide which is expected to be better tolerated in dogs. The objectives of this study were to assess the safety, the tolerability and the efficacy of intravenous etoposide phosphate in dogs with multicentric lymphoma. Seven dose levels were evaluated in a traditional 3+3 phase I design. Twenty-seven owned-dogs with high-grade multicentric lymphoma were enrolled and treated with three cycles of etoposide phosphate IV injections every 2 weeks. Adverse effects were graded according to the Veterinary Cooperative Oncology Group criteria. A complete end-staging was realized 45 days after inclusion. The maximal tolerated dose was 300 mg/m2. At this dose level, the overall response rate was 83.3% (n = 6, 3 PR and 2 CR). Only a moderate reversible gastrointestinal toxicity, no severe myelotoxicity and no hypersensitivity reaction were reported at this dose level. Beyond the characterization of etoposide clinical efficacy in dogs, this study underlined the clinical and therapeutic homologies between dog and human lymphomas.
Topics: Administration, Intravenous; Animals; Antineoplastic Agents; Dog Diseases; Dogs; Etoposide; Lymphoma; Neoplasm Grading; Neoplasm Staging; Organophosphorus Compounds; Treatment Outcome; Tumor Burden
PubMed: 28505195
DOI: 10.1371/journal.pone.0177486 -
BMJ Case Reports Jan 2020Primary pancreatic lymphoma is a rare clinical entity representing <0.5% of pancreatic cancers and 1% of extranodal lymphomas. Due to the paucity of cases described in...
Primary pancreatic lymphoma is a rare clinical entity representing <0.5% of pancreatic cancers and 1% of extranodal lymphomas. Due to the paucity of cases described in the literature, its clinicopathological features, differential diagnosis, optimal therapy and outcomes are not well defined. As the clinical manifestations are often non-specific, it can create a diagnostic pitfall for the unwary physician. Preoperative distinction of adenocarcinoma and primary pancreatic lymphoma is critical since the management and prognosis of these malignancies are mutually exclusive. Due to its rarity, epidemiological studies have been difficult to conduct. Chemotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin and vincristine) has proven to be effective. The authors present the case of a 52-year-old man with epigastric pain and obstructive jaundice. Further investigation with a CT of the abdomen and pelvis showed a low attenuation mass in the head of the pancreas measuring 35×25 mm, suspicious for malignancy. The mass involved the common bile duct distally causing moderate retrograde intrahepatic and extrahepatic biliary tree dilation of 14 mm. He underwent endoscopic retrograde cholangiopancreatography, sphincterotomy and insertion of a stent. Core biopsies confirmed the diagnosis of a high-grade B cell pancreas lymphoma. He started treatment with R-CHOP and prednisolone. Due to disease progression, he started treatment with DA-EPOCH-R (etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide, doxorubicin hydrochloride and rituximab). There was no clinical response, and treatment with RICE (rituximab, ifosfamide, carboplatin and etoposide) was initiated. He showed partial response and was under consideration for chimeric antigen receptor T cell therapy. He deteriorated clinically and succumbed to his disease 5 months following his initial presentation. This paper will provide an overview of the spectrum of haematological malignancies and describe useful features in distinguishing primary lymphoma of the pancreas from an adenocarcinoma, hence avoiding its surgical resection.
Topics: Antineoplastic Combined Chemotherapy Protocols; Diagnosis, Differential; Fatal Outcome; Humans; Lymphoma, Large B-Cell, Diffuse; Male; Middle Aged; Pancreatic Neoplasms; Rare Diseases
PubMed: 31907215
DOI: 10.1136/bcr-2019-231292 -
British Journal of Cancer Jul 2005A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II... (Clinical Trial)
Clinical Trial
A pharmacokinetically guided phase I study of topotecan and etoposide phosphate was conducted in recurrent ovarian cancer. The scheduling of the topoisomerase I and II inhibitors was determined using in vitro activity data. All patients had recurrent disease following prior platinum-containing chemotherapy. Patients had a World Health Organisation performance status of 0-2 and adequate bone marrow, renal and hepatic function. Treatment was with topotecan intravenously for 5 days followed immediately by a 5-day intravenous infusion of etoposide phosphate (EP), with pharmacokinetically guided dose adjustment. Plasma etoposide levels were measured on days 2 and 4 of the infusion. A total of 21 patients entered the study. In all, 48% were platinum resistant and 71% had received prior paclitaxel. The main toxicities were haematological, short lived and reversible. A total of 29% of patients experienced grade 4 thrombocytopenia and 66% grade 4 neutropenia after the first cycle. Neutropenia and thrombocytopenia was dose limiting. The maximum-tolerated dose was topotecan 0.85 mg m(-2) day(-1) days 1-5 followed immediately by a 5-day infusion of EP at a plasma concentration of 1 mug ml(-1). The response rate (RR) was 28% in 18 evaluable patients. There was marked interpatient variability in topoisomerase IIalpha levels measured from peripheral lymphocytes, with no observed increase following topotecan. This regimen of topotecan followed by EP demonstrated good activity in recurrent ovarian cancer and was noncrossresistant with paclitaxel. Both the toxicity and RR was higher than would be expected from the single agent data, in keeping with synergy of action.
Topics: Adult; Aged; Antigens, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; DNA Topoisomerases, Type II; DNA-Binding Proteins; Etoposide; Female; Humans; Middle Aged; Organophosphorus Compounds; Ovarian Neoplasms; Quality of Life; Recurrence; Topotecan
PubMed: 15956976
DOI: 10.1038/sj.bjc.6602657