Authors: Ramishetti Srinivas, Andrew Satterlee, Yuhua Wang...

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

Authors: R S de Jong, E A Slijfer, D R Uges...

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

Clinical Trial Randomized Controlled Trial

Authors: R S de Jong, N H Mulder, D R Uges...

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

Review

Authors: Ying-Qian Liu, Jing Tian, Keduo Qian...

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

Clinical Trial

Authors: N C Levitt, D J Propper, S Madhusudan...

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

Authors: Pierre Boyé, François Serres, Laurent Marescaux...

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

Authors: Kathryn B Vess, Nicole Ivan, Joseph Boscia...

E-cigarette-/vape-associated lung injury (EVALI) refers to damage to lung tissue occurring as a result of e-cigarette utilization or via vaping of inhaled nicotine products. Vaping refers to the practice of inhaling an aerosol derived from heating a liquid or gas containing substances such as nicotine, cannabinoids, flavoring, or additives. Battery-operated e-cigarettes or vape pens are the vessels commonly used in this practice. EVALI, first described in the literature in 2019, has a non-specific course, presenting initially with cough and dyspnea. It can progress, however, to interstitial lung disease or result in damage to the lung parenchyma with concomitant inflammation and fibrosis. Imaging findings reflect the development of this inflammation and fibrosis, often visualized as ground-glass opacities on computed tomography (CT) scans. Formal biopsies are not required to make the diagnosis of EVALI, and thus, a gap exists in the scientific literature with regard to the pathology of lungs exposed to non-tetrahydrocannabinol (THC) e-cigarettes. The following case details the clinical course of a 62-year-old male who presented to the outpatient pulmonology office with symptomology and exposure history consistent with EVALI, unique in presentation due to the timeline of his disease development. The patient initially presented to the clinic for the evaluation of a non-productive cough and exertional dyspnea beginning one year ago, with an associated new home oxygen requirement of 2 liters via nasal cannula. The patient's past medical history was relevant for diffuse large B-cell lymphoma treated with the chemotherapeutic regimen that consists of etoposide phosphate, prednisone, vincristine sulfate (Oncovin), cyclophosphamide, doxorubicin hydrochloride (hydroxydaunorubicin), and rituximab, commonly known as EPOCH-R, as well as a social history relevant for a 35-pack-year smoking history. On further questioning, the patient revealed that following cessation of cigarette smoking, he began using non-THC e-cigarettes daily and had been doing so for 10 years prior to symptom onset. Imaging and biopsy findings consisted of a CT of the chest demonstrating concern for interstitial lung disease and an open lung biopsy demonstrating diffuse alveolar damage with eosinophilia. Given the patient's history, clinical symptoms, and imaging findings, a diagnosis of EVALI was established. This case was documented not only to increase awareness of the rising incidence of EVALI as the use of e-cigarettes and vapes becomes increasingly popular but also to further understand the inhalational injury sustained from non-THC e-cigarettes and other inhalational practices.

PubMed: 38741809
DOI: 10.7759/cureus.58199

Authors: Carlo Cattrini, Matteo Capaia, Francesco Boccardo...

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

Authors: Camille Cotteret, Philippe-Henri Secretan, Laurence Gilles-Afchain...

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

Authors: H J Haisma, E Boven, M van Muijen...

The selective targeting of tumors by enzymes conjugated to monoclonal antibodies (mAb) may be an ideal approach to convert relatively nontoxic prodrugs into active agents at the tumour site. We used the anti-carcinoembryonic antigen mAb BW431/26 conjugated to alkaline phosphatase (AP) and phosphorylated etoposide (etoposide-P) as a prodrug to study the feasibility of this concept. Etoposide was phosphorylated with POCl3. Quantitative hydrolysis of etoposide-P to etoposide occurred within 10 min in the presence of AP. BW431/26 and AP were conjugated using a thioether bond. The AP conjugate retained 93% of its calculated activity. 125I-labelled AP conjugate did not show a reduction of immunoreactivity as determined by a cell-binding assay. SW1398 colon cancer cells were used to analyse the cytotoxicity of etoposide and etoposide-P. Etoposide (IC50 22 microM) was 100 times more toxic than etoposide-P (20% growth inhibition at 200 microM). Pretreatment of the cells with BW431/26-AP prior to etoposide-P exposure resulted in a dramatic increase in cytotoxicity (IC50 70 microM). The pharmacokinetics and tumour-localizing properties of BW431/27 and the AP conjugate were assessed in nude mice bearing SW1398 tumours. BW431/26 showed excellent tumour localization (10% of the injected dose/g tissue retained from 8 h to 120 h), whereas the AP conjugate showed a reduced tumour uptake (3%-0.3% of the injected dose/g tissue at 8-120 h), a faster clearance from the circulation and a high liver uptake. Radiolabelled AP showed a similar pharmacokinetic profile to the AP conjugate. Gel filtration analysis of blood, liver, and tumour samples indicated good stability of the conjugate.

Topics: Alkaline Phosphatase; Animals; Antibodies, Monoclonal; Biotransformation; Carcinoembryonic Antigen; Cell Line; Colorectal Neoplasms; Etoposide; Mice; Mice, Inbred DBA; Mice, Nude; Organophosphorus Compounds; Prodrugs; Tissue Distribution

PubMed: 1540981
DOI: 10.1007/BF01741556