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Antimicrobial Agents and Chemotherapy, September 1998, p. 2399-2404, Vol. 42, No. 9
Immunocompromised Host Section,
Received 11 August 1997/Returned for modification 25 November
1997/Accepted 16 June 1998
The activity of the pradimicin derivative BMS 181184 was evaluated
in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits and compared with that of amphotericin B
deoxycholate. BMS 181184 at total daily doses of 50 and 150 mg/kg of
body weight was at least as effective as amphotericin B at 1 mg/kg once a day in conferring survival and had comparable activity
in reducing organism-mediated tissue injury and excess lung weight.
Although treatment at all dosing regimens of BMS 181184 resulted in
significant reductions in fungal tissue burden compared to untreated
controls, equivalence to amphotericin B occurred only at the higher
dosage level. Similar observations were made in bronchoalveolar lavage fluid cultures obtained postmortem. Monitoring of the animals through ultrafast computerized tomography scan revealed a marked resolution of pulmonary lesions during treatment with BMS 181184. The
compound was well tolerated at all dosing regimens, and no toxicity was
noted. Pharmacokinetic studies revealed nonlinear drug disposition
with increased clearance at higher dosages and some evidence for
extravascular drug accumulation. BMS 181184 had excellent
activity in the treatment of experimental invasive pulmonary
aspergillosis in persistently neutropenic rabbits, thus underscoring
the potential of pradimicin derivatives in therapy of invasive
aspergillosis in the neutropenic host.
Invasive pulmonary aspergillosis is
an important cause of morbidity and mortality in immunosuppressed
patients, particularly those with hematological malignancies or
aplastic anemia or those undergoing allogeneic bone marrow
transplantation (1, 11, 15, 20, 30). Current treatment
options for neutropenic patients are limited and include amphotericin B
deoxycholate (AmB) and, more recently, lipid formulations of AmB
(28). The usefulness of AmB in this population, however, is
hampered by the drug's considerable propensity for nephrotoxicity
(24) and overall poor response rates (6). The
available lipid formulations of AmB, although better tolerated, are
still associated with failures of antifungal efficacy (12).
As a consequence, there is a continuing and urgent need for novel, more
efficacious, and less toxic therapeutic approaches.
The pradimicin family of antibiotics is a new and unique class of
compounds with broad-spectrum fungicidal activity in vitro (17). The pradimicins appear to act by calcium-dependent
complexing with the saccharide portion of cell surface mannoproteins,
leading to a perturbation of the cell membrane, leakage of
intracellular contents, and, ultimately, cell death (23).
Earlier studies indicate that the pradimicins possess very
promising, non-cross-resistant activity against
Aspergillus spp. in vitro and in animal models of
systemic infection without major limiting toxicities (8, 9, 14,
18, 19).
In order to better understand the potential use of this novel class of
compounds, we investigated the activity of a new pradimicin derivative,
BMS 181184, in a model of invasive pulmonary aspergillosis in
persistently neutropenic rabbits.
Animals.
Female New Zealand White rabbits (Hazleton, Denver,
Pa.) weighing 2 to 3 kg at the time of inoculation were used in all
experiments. They were individually housed and maintained with water
and standard rabbit feed ad libitum, according to National Institutes
of Health guidelines for laboratory animal care (4) and in
fulfillment of American Association for Accreditation of Laboratory
Animal Care criteria. Vascular access was established in each rabbit by
the surgical placement of a subcutaneous silastic central venous catheter, as previously described (26).
Immunosuppressive regimen and supportive care.
Cytosine
arabinoside (provided by Upjohn, Kalamazoo, Mich.) was administered
intravenously at 525 mg/m2 on days 1 through 5 and at 484 mg/m2 on days 8 and 9 to produce profound and persistent
neutropenia ( Organism and preparation of inoculum.
Rabbits received an
endotracheal inoculum of 5 × 107 conidia of
Aspergillus fumigatus on day 2 of the experiment after the second dose of cytosine arabinoside. A well-characterized strain of
A. fumigatus (isolate 4215) obtained from a fatal case
of pulmonary aspergillosis was used in all experiments.
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Antifungal Activity of the Pradimicin Derivative
BMS 181184 in the Treatment of Experimental Pulmonary Aspergillosis
in Persistently Neutropenic Rabbits
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
100 neutrophils per µl). Rabbits were closely
monitored by daily inspection and complete blood counts and were
treated with broad-spectrum antibiotics throughout neutropenia.
Granulocyte counts were maintained at below 500/µl and were below
100/µl from day 5 onward. Concomitant platelet counts ranged from
10,000 to 25,000/µl in most rabbits. Ceftazidime (Glaxo, Research
Triangle Park, N.C.) at 75 mg/kg of body weight intravenously twice
daily, gentamicin (Baxter Health Care Corp., Deerfield, Ill.) at 5 mg/kg intravenously daily and vancomycin (Eli Lilly, Indianapolis,
Ind.) at 15 mg/kg intravenously daily were administered from day 4 onward to prevent the emergence of invasive bacterial infections during
neutropenia.
In vitro antifungal susceptibility.
Testing of
susceptibility of the experimental isolate to both BMS 181184 and AmB
was performed by broth macro- and microdilution with an inoculum of
0.5 × 103 to 2.5 × 103 CFU/ml in
RPMI 1640 medium, as previously described (7). Tubes were
read after 24 and 48 h of incubation at 35°C. The MIC was defined as the lowest concentration of an antifungal compound which
rendered no growth (0) to slight growth (1+) on a 0 to 4+ scale. The
minimum fungicidal concentration (MFC) was determined by dispensing and
streaking 100 µl of broth from tubes exhibiting no growth onto
Sabouraud dextrose agar (Media Department, National Institutes of
Health, Bethesda, Md.) and incubating it at 35°C. The MFC was defined
as the lowest concentration of an antifungal compound with growth of
3 colonies. By this method, the MIC and MFC of BMS 181184 were 8 and
8 µg/ml, respectively, and those of AmB were 2 and 2 µg/ml.
Antifungal therapy. Four treatment groups were studied: BMS 181184 at 50 mg/kg daily in one single dose (QD) (six rabbits), BMS 181184 at 17 mg/kg three times daily (TID) (five rabbits), BMS 181184 at 150 mg/kg QD (six rabbits), and BMS 181184 at 50 mg/kg TID (six rabbits). Animals treated with AmB at 1 mg/kg QD (n = 8) and untreated but infected animals (n = 9) served as controls.
BMS 181184 (250-mg vials) (Bristol-Myers Squibb, Princeton, N.J.) was provided as a lyophilized powder, maintained at 4°C, reconstituted in 1:1 (vol/vol) sterile normal saline-sterile 5% dextrose in water to a 50-mg/ml solution and given as a slow intravenous push (2 mg/s). AmB (50-mg vials) (Fungizone; Bristol-Myers Squibb) was reconstituted with 10 cm3 of distilled water, maintained at 4°C, and diluted 1:4 (vol/vol) with sterile 5% dextrose in water immediately before use. AmB preparations were sheltered from light and administered intravenously at a rate of 0.2 mg/min after normal saline loading (10 ml/kg) to decrease nephrotoxicity. Antifungal treatment was begun 24 h after endotracheal inoculation and was administered daily throughout the experiment. Surviving rabbits were sacrificed on the 11th day postinoculation.Outcome variables. All experiments were evaluated according to the following outcome variables.
(i) Survival analysis. Duration of survival in days postinoculation was recorded for each rabbit. Surviving rabbits were euthanized by pentobarbital anesthesia on day 11 postinoculation.
(ii) Morphological and microbiological postmortem studies. The entire heart-lung block was carefully dissected and removed at autopsy. The heart was then dissected away from the lungs, leaving an intact tracheobronchial tree and lung preparation. The lungs were weighed (Mettler Instrument, Hightstown, N.J.) and inspected by two observers blinded to the treatment group who recorded the number and type of lesions, if any, in each separate lobe.
Bronchoalveolar lavage (BAL) was performed on each lung preparation by the instillation and subsequent withdrawal of 10 ml of sterile normal saline three times into the clamped trachea. A 0.1-ml sample of this fluid was cultured on Sabouraud-glucose agar. Thereafter, a representative region of each lobe was excised for cultures and histopathologic examination. Each fragment reserved for culture was weighed individually, minced with sterile scissors, and homogenized with 2 ml of sterile saline for 1 min per tissue sample in reinforced sterile polyethylene bags (Stomacher 80; Tekmar, Cincinnati, Ohio) (25). Lung homogenates in 10
2 and
104 dilutions were prepared in sterile saline, and
aliquots of 100 µl were plated onto Sabouraud-glucose agar and
incubated at 37°C for the first 24 h and then at room
temperature for another 24 h. After this, CFU of A. fumigatus were counted and recorded for each lobe and CFU per gram
were calculated. The lower limit of reproducible quantitation for this
method is 10 CFU/g. A finding of one colony of A. fumigatus was considered positive. A finding of no growth was
entered as zero in the database. In addition, the percentage of
culture-positive lobes was calculated for each rabbit.
Specimens reserved for histopathological examination were sectioned and
preserved in 10% neutral buffered formalin. The fixed specimens were
then embedded in paraffin, sectioned, stained with hematoxylin-eosin,
periodic acid-Schiff, and Gomori methenamine silver, and
microscopically examined. Hemorrhagic infarcts (dark red, consolidated
lesions) corresponded microscopically to coagulative necrosis and
intra-alveolar hemorrhage.
(iii) Radiographic studies. Serial ultrafast computerized tomography (UFCT) was performed in BMS 181184-treated rabbits in order to monitor the effects of antifungal treatment on infection-mediated tissue injury during life. Findings in untreated and AmB-treated rabbits with experimental pulmonary aspergillosis monitored by UFCT have been reported in previous studies (27).
Computerized tomography (CT) was performed with a C-100XL ultrafast electron beam CT scanner (Imatron, Oyster Point, Calif.). Rabbits were transported between the laboratory animal facility and the UFCT scanner under general anesthesia. An induction dose of a 2:1 mixture (vol/vol) of 20 mg of ketamine (Fort Dodge Laboratories) and 2 mg of xylazine (Animal Health Care Division, Mobay Corp.) was administered intravenously. General anesthesia was maintained during the procedure by an additional dose of 13 mg of ketamine and 1.3 mg of xylazine (2:1, vol/vol). Rabbits were placed prone and head first on the scanning couch. Scans were made in the high-resolution, table-increment, volume-acquisition mode. Three-millimeter-thick slices were made every 4 mm. A small scan circle and a 9-cm reconstruction circle with a 512 by 512 matrix were used, which resulted in a pixel size of less than 1 mm. Scan parameters were 130 kV at 630 mA, and scan duration was 100 ms. In virtually all cases, 30 slices were sufficient to scan the entire thorax of the rabbit. Images were photographed with lung windows with a level of
600 Hounsfield units (HU) and a width of 1,800 HU.
The radiographic course of experimental infection was followed by CT
scan on the day after inoculation and at days 5, 7, and 9 after
inoculation, if feasible. At each session, a mean pulmonary lesion
score was established by evaluating each individual rabbit's six lung
lobes. Each lobe was evaluated independently by using a score ranging
from 0 to 3 with increments of 0.5, where 0 was the absence of an
infiltrate and 3 was opacification of the entire lobe. Ultimately, the
mean pulmonary lesion score for a given day and dosage level represents
the mean of all lobes of all rabbits treated at that dosage level. All
CT scans were scored by the same observer (E.F.), who was blinded to
the identity of the study group of each rabbit.
(iv) Toxicity studies.
Blood samples were collected from
each rabbit at days 5, 7, and 9 postinoculation. Plasma samples were
stored in Sarsted tubes (Sarsted Inc., Newton, N.C.) at 70°C until
all samples were processed simultaneously. Blood urea nitrogen (BUN),
serum creatinine, potassium, and hepatic transaminase tests were
performed on the last sample drawn from each rabbit (Analytics,
Gaithersburg, Md.).
(v) Pharmacokinetic studies. Serial plasma samples were drawn from groups of three healthy rabbits each after single BMS 181184 administration of 50 mg/kg, 17 mg/kg TID, 150 mg/kg, and 50 mg/kg TID as intravenous bolus in order to determine basic pharmacokinetic parameters. An accurate, sensitive, reproducible, and specific high-performance liquid chromatography (HPLC) assay was used for the quantitative determination of BMS 181184. The method involved precipitation of plasma protein by addition of 1.2 ml of methanol to 100 µL of standard, quality controls, or unknown rabbit plasma, followed by centrifugation and removal of the methanolic layer. The methanolic supernatant was then evaporated to dryness at 40°C under a stream of nitrogen, and the sample was reconstituted in mobile phase (50 mM sterile potassium phosphate buffer-acetonitrile [80:20, vol/vol]; Fisher Scientific) for injection onto the HPLC column. BMS 181184 eluted at approximately 3.5 to 4.5 min using a C18 analytical column maintained at 35°C (Beckman Ultrasphere; Beckman Instruments, Fullerton, Calif.) and was detected by UV absorbance at 510 nm. The lower limit of quantitation of the assay was 0.2 µg/ml. Standard curves were linear from 0.2 to 200 µg/ml, and R2 values were greater than 0.97. Accuracies were within 15%, and intra- and interday variability (precision) was <10%.
Peak plasma concentrations (Cmax) represented values measured at 0.16 h after dosing. Standard techniques were used to calculate the area under the plasma concentration-time curve (AUC). Elimination half-life (t1/2), plasma clearance (CL), and volume of distribution (V) were obtained by nonlinear least-squared regression analysis after modeling the data into a two-compartment open model with the ADAPT II software program (5). Akaike's information criterion (31) and visual inspection of observed versus fitted concentrations were used for model discrimination. Weighting by the inverse of the square root of the observation variance provided the best fit of the data.Statistical analysis. Survival curves were estimated by the Kaplan-Meier product limit method, and differences between groups were analyzed by the Mantel-Haenszel chi-square test. Comparisons between proportions were done by chi-square or Fisher's exact test, and group-to-group comparisons of continuous variables were analyzed by the Kruskal-Wallis analysis of variance (ANOVA) with Dunn's correction for multiple comparisons, the Mann-Whitney U test, or t test, as appropriate. Values are stated as means ± standard deviations (SD) for pharmacokinetic parameters and as means ± standard errors of the means (SEM) for all other variables. All P values were two sided, and a P value of <0.05 was considered to be significant.
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RESULTS |
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Materials & Methods
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Discussion
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Survival. Survival among the six study groups was compared over 11 days by Kaplan-Meier analysis (Fig. 1). None of the nine untreated control rabbits survived beyond day 9 postinoculation. In contrast, 7 of 8 rabbits (88%) treated with AmB at 1 mg/kg/day survived for 11 days (P of <0.001 versus controls). Survival at day 11 postinoculation in rabbits treated with either 50 or 150 mg/kg/day was greater than that of untreated controls (P of <0.001 for both dose levels). Among the 23 rabbits treated with BMS 181184, only one did not survive until the end of the experiment (dosing regimen, 50 mg/kg QD). There was no statistically significant difference in survival between rabbits treated with BMS 181184 or AmB or among the four dosing regimens of BMS 181184.
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Postmortem morphological and microbiological studies. As shown in Fig. 2A, rabbits treated with either AmB (P < 0.001) or BMS 181184 at a total daily dosage of 50 mg/kg (P < 0.01) or 150 mg/kg (P < 0.001) had significantly fewer hemorrhagic infarcts than untreated controls. No statistically significant differences in the mean numbers of hemorrhagic infarcts were observed between BMS-treated and AmB-treated animals.
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Radiographic studies. Serial monitoring of invasive aspergillosis by UFCT in rabbits treated at total daily dosages of BMS 181184 of 50 and 150 mg/kg, respectively, revealed marked resolution of pulmonary infiltrates during the course of the experiment (Fig. 3). No dose-dependent difference was seen when the two dosage levels were compared.
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Toxicity. In comparison to untreated controls, there were no differences in the mean plasma BUN, creatinine, potassium, and hepatic transaminase levels in rabbits treated with BMS 181184 in any of the dosage groups or when dosage groups were combined for total daily dosages of 50 or 150 mg/kg/day (Table 2). In contrast, animals treated with AmB had significant increases in plasma BUN and creatinine values and significantly decreased plasma potassium compared to untreated controls and rabbits treated with BMS 181184 (data on file). Of note, rabbits receiving BMS 181184 developed variable red discoloration of body fluids and tissues.
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Pharmacokinetics. The plasma concentration-versus-time curves after administration of BMS to normal rabbits are shown in Fig. 4, and calculated values are provided in Table 3. Administration of BMS at 50 and 150 mg/kg total daily dose resulted in peak levels in plasma which were at least 20 times above both the MIC and MFC determined for the isolate of A. fumigatus used in the efficacy experiments. Increase of the dosage from 50 to 150 mg/kg QD resulted in nonproportional changes in Cmax and AUC, with increased plasma clearance (P < 0.005) and increased V (P < 0.05) at the higher dosage. Compared to QD dosing, TID administration of a total daily dose of 150 mg/kg of BMS 181184 led to an increased AUC from 0 to 24 h (AUC0-24) (P < 0.05) and apparently reduced CL.
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DISCUSSION |
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Materials & Methods
Results
Discussion
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The results of this study demonstrate potent antifungal activity of BMS 181184 in an experimental model of invasive pulmonary aspergillosis in persistently neutropenic rabbits. In comparison to untreated controls, BMS 181184 was at least as effective as standard AmB in conferring survival and had activity comparable to AmB in reducing organism-mediated tissue injury and excess lung weight postmortem. Although treatment with all regimens of BMS 181184 led to a significant reduction in fungal tissue burden, equivalence to AmB was observed only at the higher dosage level. Similar findings were noted in the microbiological analysis of BAL fluid obtained postmortem. Significant resolution of pulmonary lesions during treatment with BMS 181184 was documented by UFCT scan. In comparison to AmB-treated rabbits in this study, BMS-treated animals had no nephrotoxicity. Elevations of hepatic transaminases were not observed in any group.
Preliminary pharmacokinetic studies in uninfected animals revealed dose-dependent disposition of the drug with enhanced CL with increasing dosage. Peak plasma levels were more than 20-fold above both the MIC and MFC of the isolate of A. fumigatus used in the infection model. The V value approximated that of total body water. However, there was a marked increase in V at the 150-mg/kg QD dosage level, suggesting some form of increased extravascular drug disposition; separately submitted studies performed in our laboratories revealed that the kidney may be the site of that accumulation. Dividing the total daily dose of 150 mg/kg into a TID regimen resulted in a trend toward diminished clearance and increased AUC0-24 compared to QD administration; a possible explanation for this observation would be the existence of a saturable tubular reabsorption process and/or saturable protein binding, leading to an increased renal CL of the compound after bolus administration of higher dosages.
The requirement of relatively high doses of BMS 181184 for effective
treatment of invasive aspergillosis correlates with the relatively high
MIC and MFC values compared to those of AmB. By the broth macrodilution
reference methods recommended by the National Committee for Clinical
Laboratory Standards, MICs for all six A. fumigatus
strains and one strain of Aspergillus nidulans tested were 8 µg/ml. Aspergillus flavus (n = 3) and
A. niger (n = 4) were slightly less
susceptible (MICs, 
16 µg/ml). Whereas AmB was fungicidal against
all of the nine Aspergillus strains tested, BMS 181184 reduced cell counts for only six of the nine strains on the basis of
MFCs at which 95% of the isolates were killed (MFC95) and
MFC90, which were within twofold of the MICs
(8). By comparison, MICs of BMS 181184 for >95% of all
yeasts tested were 8 µg/ml (8, 13), and in all strains
tested, the compounds' MFC99 were no more than twofold
greater than the MICs (8). With a related, RPMI-based
macrodilution method, geometric mean MICs for 54 isolates of
Aspergillus were 9.08 µg/ml (range, 4 to 16 µg/ml).
BMS 181184 was fungicidal (killing of 98%) in only 37% of
isolates tested. Susceptibilities varied between species, with
A. fumigatus (n = 35) being the most
susceptible to the drug (geometric mean MIC, 7.99; range, 4 to 16 µg/ml) (16). The observed differences in susceptibility
may be plausibly correlated with inter- and intraspecies differences in
cell wall mannoprotein content. Whereas the cell walls of yeasts in
general contain abundant amounts of these molecules, they are expressed
only in traces in some of the filamentous fungi (2, 8).
The requirement of higher doses of BMS 181184 for effective treatment of invasive aspergillosis is also obvious from the available preclinical data. After a single intravenous bolus dose immediately after intravenous inoculation into normal mice, the calculated protective dose of BMS 181184 necessary to ensure 50% survival at 20 days (PD50) was 8.8 and 31 mg/kg for Candida albicans and A. fumigatus, respectively. In cyclophosphamide-treated animals, the PD50 was substantially higher, increasing to 31 mg/kg in C. albicans and to >50 mg/kg in A. fumigatus. However, when the drug was given for two consecutive days after inoculation, the PD50 for A. fumigatus dropped to 23 mg/kg, resulting in survival of 80% of animals with a dose of 50 mg/kg (19).
In a model of systemic aspergillosis in transiently neutropenic rabbits, BMS 181184 was given at 50 mg/kg QD, 75 mg/kg QD, and 50 mg/kg TID starting 24 h after intravenous challenge for five consecutive days. Whereas the infection was uniformly lethal in untreated controls, survival in BMS-treated rabbits increased in a dose-dependent manner from 27 to 57 and 100%, respectively. Significant reduction of fungal burden in liver and kidney but not lung was observed with 50 mg/kg TID. However, although mortality was high (67%), microbiological efficacy was highest and most consistent in rabbits treated with AmB (1 mg/kg) (21). BMS 181184 has also been compared to itraconazole as the reference azole in mice rendered immunocompromised by triamcinolone and challenged systemically with A. fumigatus. Whereas BMS 181184 (25 mg/kg) and AmB (0.8 mg/kg) increased the survival time in comparison to untreated controls, itraconazole (100 mg/kg) was not effective. BMS 181184 was superior to itraconazole but less active than AmB in clearing tissue (3).
A high therapeutic index permits the administration of relatively large doses of BMS 181184 to animals with minimal toxicity. In comparison with AmB, the compound was 40- to 50-fold less active but at least 130-fold less toxic on a milligrams-per-kilogram basis (19). Although reversible granulomatous inflammation in various tissues in rats and dogs, renal tubular degeneration in dogs at high doses not associated with any renal function test abnormalities, and apparently species-specific hemolysis in Cynomolgus monkeys at high doses have been found in unpublished toxicity studies (29), we and other investigators (10, 21, 22) did not observe significant toxicities at the doses used in the experiments, except for red discoloration of body fluids and some tissues.
In conclusion, BMS 181184 was well tolerated and demonstrated efficacy comparable to that of AmB in a model of invasive pulmonary aspergillosis in persistently neutropenic rabbits closely resembling conditions of human infection. Although early phase I studies in human volunteers revealed hepatic toxicity associated with BMS 181184, perhaps less-toxic congeners of this promising family of antifungal antibiotics with identical or even improved therapeutic efficacy against invasive pulmonary aspergillosis will be developed.
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ACKNOWLEDGMENTS |
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We express our gratitude to Kristina Kligys and William Love for excellent technical assistance.
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FOOTNOTES |
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* Corresponding author. Mailing address: Immunocompromised Host Section, Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Building 10, Room 13N240, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 402-0023. Fax: (301) 402-0575. E-mail: twalsh{at}pbmac.nci.nih.gov.
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Materials & Methods
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Discussion
References
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