Successful rechallenge with etoposide phosphate after an acute hypersensitivity reaction to etoposide.

Hypersensitivity reactions to etoposide are reported infrequently and consist of hypotension, hypertension, flushing, diaphoresis, dyspnea, bronchospasm, and loss of consciousness. A 23-year-old woman experienced acute bronchospasm, tachycardia, hypoxia, and moderate hypertension minutes after an infusion of etoposide was begun. Symptoms resolved within an hour after administration of intravenous fluids, methylprednisolone, diphenhydramine, and oxygen. Subsequently, the patient was given etoposide phosphate without incident. To our knowledge, this is the first report of successful rechallenge with etoposide phosphate after an acute hypersensitivity reaction to etoposide.     

Oral etoposide

Etoposide, a semisynthetic derivative of podophyllotoxin, has been commercially available for intravenous use for a number of years, and has been used as part of first-line combination chemotherapy programs for small cell lung cancer (SCLC). It has also been used to treat testicular cancer, non-small cell lung cancer, and a variety of other malignancies. Etoposide for oral use has become commercially available and is approved for use in the treatment of SCLC. Although no clinical trials comparing intravenous and oral etoposide in SCLC have been reported, several pharmacokinetic studies have been described. These studies have demonstrated a mean bioavailability of 50 percent, with a wide range among patients. Other pharmacokinetic parameters are similar for both the intravenous and oral methods of administration. Based on these results, the recommended dose of oral etoposide is twice the intravenous dose. Oral etoposide has been demonstrated to be effective in the treatment of SCLC. It offers a reasonable and cost-effective outpatient alternative for this group of patients.     

Etoposide phosphate, the water soluble prodrug of etoposide

Etoposide (Vepesid) is a widely used drug in a variety of neoplasms. To improve the pharmaceutical characteristics of etoposide, etooside phosphate (Etopophos, Bristol-Myers Squibb) has been developed as a prodrug.Etoposide phosphate is the phosphate ester derivative of etoposide, in comparison to the parent compound, etoposide phosphate is highly soluble in water and can be readily formulated for intravencus uso resulting in higher ctinical application. This paper presents information on the pharmaceutical properties and the current status of etoposide phosphate in clinical triafs.     

Phase I study of high dose etoposide phosphatase with filgrastim (G-CSF) in the treatment of advanced refractory malignancies

Purpose: To define the maximum tolerated dose of etoposide phosphate when used with G-CSF in the treatment of patients with refractory malignancies.Patients and methods: Eleven patients with advanced cancer refractory to standard therapy were treated with etoposide phosphate given over 1–2 hours on three consecutive days. The first cohort of patients received a total dose of 1596 mg/m² (equivalent to etoposide 1400 mg/m²); doses were escalated in subsequent patient cohorts. G-CSF 5 µg/kg was administered subcutaneously from day 4 until the total leukocyte count rose to > 10,000/µL. Two courses were given at 28 day intervals.Results: Toxicity produced by high dose etoposide phosphate included myelosuppression and mucositis. Three of five patients treated at the 2280 mg/m² dose level (equivalent to etoposide 2000 mg/m²) had dose limiting toxicities (grade 4 leukopenia for 7 days, 2 patients; grade 4 mucositis + leukopenia, 1 patient). In addition, median days with severe thrombocytopenia (< 50,000/µL) rose to six days at this dose. Other toxicity was uncommon.Conclusions: In pretreated patients, the maximum tolerated dose of etoposide phosphate with G-CSF is 1938 mg/m² (equivalent to etoposide 1700 mg/m²). Dose-limiting toxicities were myelosuppression and mucositis, as with high dose etoposide. Etoposide phosphate can be substituted for etoposide in high dose regimens; due to its greater solubility, administration can be more rapid, requires less fluid volume, and is not associated with acidosis.     

Risks and mitigation strategies to prevent etoposide infusion-related reactions in children

Etoposide is an antineoplastic agent widely used for treatment of many pediatric cancers. Etoposide has been associated with infusion-related reactions. In this brief report, we compare etoposide infusion-related reactions that occurred over a 10-year period at two freestanding pediatric hospitals. Infusion reactions occurred in 1% of patients at two hospitals across the study period. Rates of 4.8%, 3.4%, and 7.9% were observed at Children's Mercy Hospital during 2018, 2019, and 2020, respectively, after the implementation of in-line filters during etoposide infusions in late 2017. Of the 32 patients who experienced adverse reactions, 41% were rechallenged after the reaction and all were able to tolerate at least one future dose with either pre-treatment or extending infusion duration. This work highlights the importance of a multicenter approach to investigating adverse drug reactions (ADRs) as variation in practice can provide key information about ADRs and potential risk factors.     

Limited and optimal sampling strategies for etoposide and etoposide catechol in children with leukemia

Etoposide is used to treat childhood malignancies, and its plasma pharmacokinetics have been related to pharmacodynamic endpoints. Limiting the number of samples should facilitate the assessment of etoposide pharmacokinetics in children. We compared limited sampling strategies using multiple linear regression of plasma concentrations and clearance with Bayesian methods of estimating clearance using compartmental pharmacokinetic models. Optimal sampling times were estimated in the multiple linear regression method by determining the combination of two samples which maximized the correlation coefficient, and in the Bayesian estimation approach by minimizing the variance in estimates of clearance. Clearance estimates were compared to the actual clearances from Monte Carlo-simulated data and predicted clearances estimated using all available plasma concentrations in clinical data from children with acute lymphoblastic leukemia. Multiple linear regression poorly predicted clearance (mean bias 8.3%, precision 17.5%), but improved if plasma concentrations were logarithmically transformed (mean bias 1.4%, precision 12.5%). Bayesian estimation methods with optimal samples gave the best overall prediction (mean bias 2.5%, precision 6.8%) and also performed better than regression methods for abnormally high or low clearances. We conclude that Bayesian estimation with limited sampling gives the best estimates of etoposide clearance.     

Myeloperoxidase-catalyzed metabolism of etoposide to its quinone and glutathione adduct forms in HL60 cells

Etoposide is a widely used antineoplastic agent that has provided great success in the treatment of childhood leukemias and other malignancies. Unfortunately, its use is associated with the increased risk of development of secondary acute myelogenous leukemias involving translocations at the MLL gene in chromosome band 11q23. Previous studies showed that the phenoxyl radical of etoposide can be generated by myeloperoxidase (MPO), an enzyme prevalent in myeloid progenitor cells that can derive myelogenous leukemias. Disproportionation of this radical leads to formation of the redox active etoposide ortho-quinone metabolite. We hypothesized that etoposide ortho-quinone could therefore form in myeloid progenitor cells and might be a contributor to the development of treatment-related secondary leukemias. Etoposide ortho-quinone is an inherently unstable compound and readily reacts with glutathione in aqueous media without any requirement for catalytic assistance from glutathione S-transferase. We looked for the presence of its glutathione adduct as an indicator of etoposide ortho-quinone in cells. MPO-expressing human myeloid leukemia HL60 cells were treated with etoposide for 0.5 h in the presence and absence of the cosubstrate of MPO, hydrogen peroxide. Cell lysates and medium were analyzed by LC-ESI-ion trap-MS and MS/MS, which yielded clear evidence of the intracellular formation of the etoposide ortho-quinone-glutathione adduct. A stable isotope-labeled form of the GSH adduct was synthesized and employed as an isotope dilution internal standard in LC-ESI-quadrupole-MS analyses. The glutathione adduct level was dependent on the concentration of etoposide added to the cells. More importantly, the formation of the glutathione adduct was significantly suppressed by the pretreatment of HL60 cells with the heme synthesis inhibitor succinylacetone (p < 0.001), which resulted in a decreased level and activity of MPO. These results are consistent with the idea that MPO is responsible for the conversion of etoposide to its ortho-quinone in these cells.     

Compatibility of etoposide phosphate with selected drugs during simulated Y-site injection

OBJECTIVE: To evaluate the physical compatibility of etoposide phosphate with 101 selected secondary drugs, including antineoplastic chemotherapy agents, anti-infectives, and supportive care drugs, during simulated Y-site injection. DESIGN: Five-milliliter samples of etoposide 5 mg/mL as phosphate in 5% dextrose injection were mixed with 5 mL of the selected drugs diluted in 5% dextrose injection or, if necessary to avoid incompatibilities with the diluent, 0.9% sodium chloride injection. Samples were examined visually in normal fluorescent light with the unaided eye and using a Tyndall beam (high-intensity monodirectional light) to enhance the visibility of small particles and low-level haze. Turbidity of each sample was measured. In selected samples, electronic particle content assessment was performed. All of the samples were assessed initially and at one and four hours. RESULTS: Most of the secondary drugs were physically compatible with etoposide phosphate during the four-hour observation period. However, seven drug combinations had incompatibilities that included color change, increase in haze or turbidity, particulate formation, and gross precipitation. The drugs that were observed to be physically incompatible with etoposide phosphate were amphotericin B, cefepime hydrochloride, chlorpromazine hydrochloride, imipenem-cilastatin sodium, methylprednisolone sodium succinate, mitomycin, and prochlorperazine edisylate. CONCLUSION: Etoposide 5 mg/mL as phosphate in 5% dextrose injection is physically compatible for four hours at room temperature during simulated Y-site administration with 94 of the 101 drugs selected. Simultaneous Y-site administration of etoposide phosphate with the seven incompatible drugs should be avoided.     

Kinetics and regulation of cytochrome P450-mediated etoposide metabolism.

Etoposide is a DNA topoisomerase II inhibitor widely used in the treatment of a variety of malignancies that is also associated with therapy-related leukemia. The cytochrome P450 (P450)-derived catechol and quinone metabolites of etoposide may be important in the damage to the MLL (mixed lineage leukemia) gene and other genes resulting in leukemia-associated chromosomal translocations. Kinetic analysis of catechol formation by recombinant P450s was determined using liquid chromatography/selected reaction monitoring/mass spectrometry. CYP3A4 was found to play a major role in etoposide metabolism (K(m) = 77.7 +/- 27.8 microM; V(max) = 314 +/- 84 pmol of catechol/min/nmol of P450). However, CYP3A5 (K(m) = 13. 9 +/- 3.1 microM; V(max) = 19.4 +/- 0.4 pmol of catechol/min/nmol of P450) may be involved in etoposide metabolism at therapeutic concentrations of free drug. Other P450s do not appear to be involved in etoposide catechol formation. Real-time polymerase chain reaction and Western blot analysis revealed significantly increased CYP3A4 mRNA and protein levels in hepatocytes treated with 10 microM rifampicin compared with untreated cells, but only modest effects of rifampicin on CYP3A5 induction. Etoposide (40, 5, 1, and 0.25 microM) caused a slight increase in CYP3A4 mRNA in three of five batches of hepatocytes but did not result in proportionately increased CYP3A4 protein levels. At high concentrations, etoposide induced only a modest increase in CYP3A5 mRNA and protein levels in four of five batches of hepatocytes. Alternatively, coadministration of other drugs with etoposide may account for the increase in etoposide catechol formation during therapy with etoposide.     

Physical and chemical stability of etoposide phosphate solutions

OBJECTIVE: To evaluate the physical and chemical stability of etoposide phosphate solutions over 7 days at 32 degrees C and 31 days at 4 degrees C and 23 degrees C: (1) at etoposide concentrations of 0.1 and 10 mg/mL as phosphate in 0.9% sodium chloride injection and 5% dextrose injection and (2) at etoposide concentrations of 10 and 20 mg/mL as phosphate in bacteriostatic water for injection packaged in plastic syringes. DESIGN: Test samples of etoposide phosphate were prepared in polyvinyl chloride (PVC) bags of the two infusion solutions at etoposide concentrations of 0.1 and 10 mg/mL as phosphate. Additional test samples were prepared in bacteriostatic water for injection containing benzyl alcohol 0.9% at etoposide concentrations of 10 and 20 mg/mL as phosphate and were packaged in 5 mL plastic syringes. Evaluations for physical and chemical stability were performed initially; after 1 and 7 days of storage at 32 degrees C; and after 1, 7, 14, and 31 days of storage at 4 degrees C and 23 degrees C. Physical stability was assessed using visual observation in normal light and using a high-intensity monodirectional light beam. Turbidity and particle content were measured electronically. Chemical stability of the drug was evaluated by using a stability-indicating high-performance liquid chromatographic (HPLC) analytic technique. RESULTS: All samples were physically stable throughout the study. Little or no change in particulate burden and haze level were found. In the intravenous infusion solutions, little or no loss of etoposide phosphate occurred in any of the samples throughout the study period. The 10 and 20 mg/mL samples in bacteriostatic water for injection repackaged in syringes were also stable throughout the study, exhibiting a maximum of 6% or 7% loss after 31 days of storage at 23 degrees C and less than 4% in 31 days at 4 degrees C. CONCLUSION: Etoposide phosphate prepared as intravenous admixtures of etoposide 0.1 and 10 mg/mL as phosphate in 5% dextrose injection and 0.9% sodium chloride injection in PVC bags and as etoposide 10 and 20 mg/mL as phosphate in bacteriostatic water for injection packaged in plastic syringes is physically and chemically stable for at least 7 days at 32 degrees C and 31 days at 4 degrees C and 23 degrees C. This new water-soluble phosphate-ester of etoposide formulation solves the precipitation problems associated with the old organic solvent and surfactant-based formulation.     

Bioequivalence assessment of etoposide phosphate and etoposide using pharmacodynamic and traditional pharmacokinetic parameters

The bioequivalence of etoposide phosphate, a prodrug of etoposide, to etoposide was assessed in a randomized, crossover study in 29 patients with histologically established solid tumors that had failed conventional treatment. Cohorts of patients received one treatment course each of etoposide and etoposide phosphate which consisted of a 100 mg/m² per day etoposide equivalent dose infused iv over 1 hr on a Day 1 to 5 schedule of treatment. The second course was administered 21 days later or on recovery of blood cell counts. Plasma and urine samples were collected over 24 hr on Day 1 of each course and assayed for etoposide content by a validated HPLC/UV method. Resulting data were subjected to noncompartmental pharmacokinetic analysis. Hematology profiles were obtained by collecting blood samples prior to the first course and twice a week after each course. The pharmacodynamics and pharmacokinetics of etoposide were virtually identical after the two treatments. The point estimates (90% confidence intervals) for nadir WBC, granulocytes, hemoglobin, and platelets expressed as % decrease from the baseline, and for the pharmacokinetic parameters, C_max, and AUC_0-∞, after intravenous etoposide phosphate relative to etoposide were 100% (96%, 105%), 97% (91%, 103%), 95% (82%, 109%), 95% (84%, 106%), 107% (101%, 113%), and 113% (107%, 119%), respectively. Therefore, etoposide phosphate is bioequivalent to etoposide based on pharmacokinetic and pharmacodynamic assessments.     

Oral etoposide in lymphoma

Etoposide is one of the most active agents for the therapy of lymphomas. Oral etoposide has proven to be active in and clearly beneficial for patients with previously treated lymphomas. The optimal dose and schedule of oral etoposide for use in combination chemotherapy are still uncertain, but low daily doses (50 to 100 mg) for 10 to 14 days may be near optimal. Studies in previously untreated patients using combination chemotherapy that includes oral etoposide are needed, since preliminary data suggest that this agent has excellent activity and tolerability when combined or alternated with methotrexate, calcium folinate (calcium leucovorin), cyclophosphamide, vincristine, and prednisone in the elderly and medically unfit patient. Combination therapy approaches may also be helpful in HIV-related lymphomas. Additional studies are warranted.     

Oral etoposide in germ cell tumours

Patients with germ cell tumours who relapse or fail to achieve disease-free status after first-line chemotherapy have a poor prognosis. When administered orally, etoposide produces responses in approximately 25% of patients whose disease is refractory to therapy and is a reasonable choice for palliative treatment in patients who are otherwise incurable. Oral etoposide has also been studied as maintenance therapy in patients who have been treated with salvage chemotherapy or surgery, with results that compare favourably with historical data. We recommend 3 months of maintenance oral etoposide for patients who achieve a complete response to any type of salvage therapy.     

The clinical pharmacology of etoposide and teniposide

Etoposide and teniposide are semisynthetic derivatives of podophyllotoxin and are increasingly used in cancer medicine. Teniposide is more highly protein-bound than etoposide, and its uptake and binding to cells is also greater. Etoposide and teniposide are phase-specific cytotoxic drugs acting in the late S and early G2 phases of the cell cycle. They appear to act by causing breaks in DNA via an interaction with DNA topoisomerase II or by the formation of free radicals. Teniposide is more potent as regards the production of DNA damage and cytotoxicity. Most studies show a biexponential decay following intravenous administration of etoposide and teniposide. The terminal elimination half-life of etoposide is less than that of teniposide, and the plasma and renal clearances of etoposide are greater. The peak plasma concentrations of drug and the area under the concentration versus time curve are linearly related to the intravenous dose of both drugs. Considerable interpatient variability of pharmacokinetic parameters exists following intravenous etoposide and teniposide. Various metabolites of etoposide and teniposide have been identified but their detection and quantitation are disputed. Approximately 30 to 70% of a dose of etoposide is accounted for by excretion, whereas the figure appears to be only 5 to 20% for teniposide. The bioavailability of oral etoposide is about 50% but its absorption is not linear with increasing dose within the range in clinical use. There is considerable inter- and intrapatient variability in the pharmacokinetics of oral etoposide. There is no evidence of accumulation of etoposide and teniposide after multiple consecutive doses by the intravenous or oral routes. The exact roles of the liver and kidney in metabolism and excretion of etoposide and teniposide are uncertain. Etoposide has been shown to be a highly schedule-dependent drug in clinical studies. This together with the phase-specific action of etoposide and teniposide and their increasingly widespread use in cancer medicine make the clinical pharmacology of these drugs of great clinical importance.     

Factors affecting in vitro protein binding of etoposide in humans.

Clinical studies have demonstrated that the plasma protein binding of etoposide, a widely used anticancer drug, is extensive (approximately 94%), highly variable among patients (10-fold range), and significantly related to serum albumin and total bilirubin concentration. The present study was designed to more thoroughly evaluate factors likely to affect etoposide protein binding under controlled in vitro conditions where single variables could be changed. Protein binding was determined using an equilibrium dialysis method with tritiated etoposide. The binding of etoposide was similar in serum or plasma, and heparin had no effect on binding. Etoposide binding decreased with increased pH, but no clinically significant difference was noted within the range of physiologic pH. Etoposide binding evaluated in single-source donor plasma was concentration-dependent over a concentration range of 1 to 250 micrograms/mL. Etoposide binding parameters determined in normal human plasma were characterized by a single class of binding sites of moderate affinity (K = 2.88 +/- 0.47 x 10(4)) and high capacity (nP = 5.07 +/- 0.5 x 10(-4); where n is the number of binding sites). The etoposide binding ratio was significantly correlated with albumin concentration (r2 = 99%, p less than 0.05). The characteristics of etoposide binding in a 4.0-g/dL solution of human serum albumin (K = 3.56 +/- 1.22 x 10(4) and nP = 5.58 +/- 0.16 x 10(-4)) suggest that the single class of binding sites is on albumin. Bilirubin caused a significant decrease in K, consistent with competitive binding, but only at higher bilirubin concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myeloperoxidase-dependent oxidation of etoposide in human myeloid progenitor CD34+ cells

Etoposide is a widely used anticancer drug successfully used for the treatment of many types of cancer in children and adults. Its use, however, is associated with an increased risk of development of secondary acute myelogenous leukemia involving the mixed-lineage leukemia (MLL) gene (11q23) translocations. Previous studies demonstrated that the phenoxyl radical of etoposide can be produced by action of myeloperoxidase (MPO), an enzyme found in developing myeloid progenitor cells, the likely origin for myeloid leukemias. We hypothesized, therefore, that one-electron oxidation of etoposide by MPO to its phenoxyl radical is important for converting this anticancer drug to genotoxic and carcinogenic species in human CD34(+) myeloid progenitor cells. In the present study, using electron paramagnetic resonance spectroscopy, we provide conclusive evidence for MPO-dependent formation of etoposide phenoxyl radicals in growth factor-mobilized CD34(+) cells isolated from human umbilical cord blood and demonstrate that MPO-induced oxidation of etoposide is amplified in the presence of phenol. Formation of etoposide radicals resulted in the oxidation of endogenous thiols, thus providing evidence for etoposide-mediated MPO-catalyzed redox cycling that may play a role in enhanced etoposide genotoxicity. In separate studies, etoposide-induced DNA damage and MLL gene rearrangements were demonstrated to be dependent in part on MPO activity in CD34(+) cells. Together, our results are consistent with the idea that MPO-dependent oxidation of etoposide in human hematopoietic CD34(+) cells makes these cells especially prone to the induction of etoposide-related acute myeloid leukemia.     

The effect of etoposide on influx and efflux of cytosine arabinoside in P388 murine leukemic cells]

We studied the effects of etoposide on the influx, intracellular accumulation and efflux of ara-C in P388 leukemic cells. Etoposide inhibited the active influx of ara-C in a dose dependent manner, and the inhibition was reversible. Etoposide also affected the intracellular accumulation of ara-C, though its inhibitory effect for the intracellular accumulation was weaker than that for the influx of ara-C. It was also shown that etoposide inhibited the active efflux of ara-C. Furthermore, etoposide inhibited the active transport of ara-C bidirectionally but the insensitive route of etoposide existed especially at high concentration of ara-C. The effect of inhibition of the transport of ara-C on the accumulation of ara-C was more significant at lower concentration of ara-C. Judging from the drug concentrations used in this study, an interaction between etoposide and ara-C could occur in the clinical treatment.     

Pharmacokinetic optimisation of treatment with oral etoposide

Etoposide is a derivative of podophyllotoxin widely used in the treatment of several neoplasms, including small cell lung cancer, germ cell tumours and non-Hodgkin's lymphomas. Prolonged administration of etoposide aims for continuous inhibition of topoisomerase II, the intracellular target of etoposide, thus preventing tumour cells from repairing DNA breaks. However, the clinical advantages of extended schedules as compared with conventional short-term infusions remain unclear. Oral administration of etoposide represents the most feasible and economic strategy to maintain effective concentrations of drug for extended times. Nevertheless, the efficacy of oral etoposide therapy is contingent on circumventing pharmacokinetic limitations, mainly low and variable bioavailability. Inhibition of small bowel and hepatic metabolism of etoposide with specific cytochrome P450 inhibitors or inhibition of the intestinal P-glycoprotein efflux pump have been attempted to increase the bioavailability of oral etoposide, but the best results were obtained with daily oral administration of low etoposide doses (50-100 mg/day for 14-21 days). Saturable absorption of etoposide was reported for doses greater than 200 mg/day, whereas lower doses were associated with increased bioavailability, although they were characterised by high inter- and intrapatient variability. Pharmacokinetic parameters such as plasma trough concentration between two oral administrations (C(24,trough)), drug exposure time above a threshold value and area under the plasma concentration-time curve have been correlated with the pharmacodynamic effect of oral etoposide. Pharmacokinetic-pharmacodynamic relationships indicate that severe toxicity is avoided when peak plasma concentrations do not exceed 3-5 mg/L and C(24,trough) is under the threshold limit of 0.3 mg/L. To maintain effective etoposide plasma concentrations during prolonged oral administration, pharmacokinetic variability must be monitored in each patient, taking account of factors from many pharmacokinetic studies of etoposide, including absorption, distribution, protein binding, metabolism and elimination. Dosage reduction is generally useful to avoid haematological toxicity in patients with renal dysfunction (creatinine clearance <50 mL/min). The need for dosage adjustment based on liver function in patients with liver dysfunction is not completely defined, but generally is not indicated in patients with minor liver dysfunction. Adaptive dosage adjustment based on individual pharmacokinetic parameters, estimated using limited sampling strategies and population pharmacokinetic models, is more appropriate. This approach has been used with success in different clinical trials to increase the etoposide dosage, without significantly increasing toxicity. Various pharmacodynamic models have been proposed to guide etoposide oral dosage. However, they lack precision and accuracy and need to be refined by considering other predictor variables in order to extend their application in current clinical practice.     

The mechanism of synergistic interaction between etoposide and cytarabine

The sequence dependency of the antitumor effect of etoposide and cytarabine (ara-C) was investigated against the L1210 ascites tumor in BDF1 mice. Etoposide (7.5 mg/kg or 15 mg/kg) and ara-C (25 mg/kg or 500 mg/kg) were administered intraperitoneally on days 1, 4, and 7 after inoculation of L1210 cells with or without a time interval of 3 or 6 h. Simultaneous administration of etoposide and ara-C produced a 70% cure rate. At every dosage examined, pretreatment with etoposide given 6 h before ara-C was the most effective antitumor schedule in L1210 leukemia. At 1 h after injection of ara-C, 3 h and 6 h pretreatment with etoposide 15 mg/kg increased ara-C incorporation to more than 200% as compared with that of ara-C given alone. Simultaneous administration of etoposide, however, decreased ara-C incorporation to 33% of that of ara-C alone. Deoxycytidine kinase (dCK) is a rate-limiting enzyme for the activation of ara-C. We demonstrated that dCK activity was increased within 1 h after exposure to etoposide. Much more attention must be paid to the timing of the administration of etoposide in combination chemotherapy with etoposide and ara-C.     

Enhanced delivery of etoposide to Dalton's lymphoma in mice through polysorbate 20 micelles

The study evaluates the possibility of enhancing uptake of etoposide (topoisomerase II inhibitor) by tumor when delivered through polysorbate 20 micelles. The micelle formation was ascertained by determining the critical micellar concentration (CMC) with a du Nouy ring tensiometer and by size measurement using dynamic light scattering. Addition of 5% ethanol decreased the CMC of Polysorbate 20 (from 5.0 x 10(-5) to 4.54 x 10(-5) mol L(-1)). Etoposide (ET) and etoposide loaded polysorbate 20 micelles (EPM) were radiolabeled with 99mTc by the reduction method using stannous chloride. Labeling parameters were optimized to obtain high labeling efficiency. The diethylenetriaminepentaacetic acid and cysteine challenge tests showed very low transchelation of 99mTc-ET and 99mTc-EPM complexes indicating their in vitro stability. The complexes also exhibited serum stability assessed by ascending thin layer chromatography. Subcutaneous injection of EPM resulted in significantly higher tumor uptake ( 100 folds compared to ET 6 h post injection) (p < 0.001) and prolonged tumor retention. Tumor uptake was also confirmed by gamma imaging studies. EPM exhibited relatively high brain concentrations ( 7 fold 24 h post injection) compared to ET, suggesting the potential use of EPM in the treatment of brain malignancies.