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Experimental Therapeutics, Preclinical Pharmacology |
Departments of Neurology [L. L. M., R. A. K., N. D. D., E. A. N.], Biochemistry and Molecular Biology [E. A. N.], Pharmacology [R. E. B.], and Cell and Developmental Biology [L. L. M.], and Division of Neurosurgery [E. A. N.], Oregon Health Sciences University, Portland, Oregon 97201; Department of Otolaryngology, Oregon Hearing Research Center, Portland, Oregon 97201 [R. E. B.]; Veterans Administration Medical Center, Portland Oregon 97201 [E. A. N., M. A. P.]; Greenbaum Cancer Center and Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201 [E. G. Z., M. J. E.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Ototoxicity has a significant negative impact on patient quality of life. Mechanisms to decrease this undesirable effect would increase the use of the effective platinum-based chemotherapeutic agents. A possible solution to the problem of platinum ototoxicity may be the use of a chemoprotective agent (9) . At high molar excess, STS binds to, and inactivates, cisplatin and carboplatin in vitro (10 , 11) , and STS reduces cisplatin nephrotoxicity in animal models (12) and in patients (13 , 14) . We have explored STS as an otoprotective agent. In a guinea pig model, we previously showed that high doses of STS reduced carboplatin-mediated cochlear damage, as confirmed by electrophysiological measurements and histology (8) . In patient studies, blood concentrations of STS equivalent to those in the guinea pig model could not be achieved due to transient hypernatremia and hypertension (15) . Nevertheless, significant otoprotection was demonstrated when STS was given 2–8 h after administration of carboplatin with osmotic BBB disruption in brain tumor patients (15) .
A possible drawback to the use of a chemoprotectant is its potential to interact with and reduce the desired antitumor effects of carboplatin or cisplatin. Two-route therapy has been used in studies of cisplatin and STS to provide high local antitumor activity with systemic chemoprotection (12 , 13 , 14) . For example, the combination of i.p. administration of high-dose cisplatin with i.v. administration of STS has shown favorable results against ovarian cancer, allowing dose escalation while decreasing the nephrotoxicity of the drug (13 , 14) . Studies of STS in brain tumor patients made use of the two compartments generated by the presence of the BBB. Carboplatin was delivered to intracerebral tumors with transient osmotic BBB disruption, whereas STS, administered after the BBB permeability returned to normal, was used to reduce the systemic toxicity and ototoxicity of the drug remaining in the peripheral circulation (15) .
Another alternative to avoid interactions of the platinum chemotherapeutic and the chemoprotective agent is to separate their administration in time. Previous studies of STS with cisplatin showed that the STS had to be administered within 5 min of the cisplatin to be effective at reducing nephrotoxicity (9 , 13 , 14) . In contrast, STS was effective at reducing carboplatin ototoxicity when administered up to 8 h after carboplatin in the guinea pig (8) . In the clinical brain tumor trial described above (15) , STS was separated from carboplatin both by two compartments, and by time, in that STS was administered after the BBB closed, at 2 h after carboplatin.
The current studies were undertaken to determine whether the delayed administration of STS impacts carboplatin antitumor efficacy. Additionally, we evaluated the potential for delayed STS rescue of cisplatin ototoxicity. Our goal is to reduce the ototoxicity of platinum chemotherapeutics without a decrease in tumor cytotoxicity.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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s.c. Tumor Efficacy Studies.
Animal studies were performed in accordance with guidelines established
by the Oregon Health Sciences University Committee on Animal Care and
Use. The LX-1 human small cell lung carcinoma cell line (originally
obtained from Mason Research Institute, Worcester, MA) was maintained
as a free-floating cell suspension in spinner flasks, in RPMI 1640
supplemented with 10% heat-inactivated fetal bovine serum (Irvine
Scientific, Santa Ana, CA) plus gentamicin, penicillin, and
streptomycin. Cell suspensions with viability >90% by trypan blue
exclusion and packed cell volumes of 20% ± 1% (
1 x
105 cells/µl) were used for tumor implantation.
Adult, female nude rats from a colony maintained at Oregon Health
Sciences University and weighing 220–240 g were briefly anesthetized
with nitrous oxide and isoflurane inhalant (Isothesia; Abbott
Laboratories, North Chicago, IL), and 600 µl of LX-1 cell suspension
were inoculated into the s.c. tissue of the right flank.
Therapy studies were initiated 24 h after tumor cell inoculation. The rats were anesthetized with 2% isoflurane for placement of an i.v. catheter in the femoral vein, then anesthetized with propofol (650 µg/kg/min; Zeneca Pharmaceuticals, Wilmington, DE) as a constant infusion during the remainder of the treatment, as described previously (16) . The right external carotid artery was surgically exposed and catheterized for infusion of carboplatin (200 mg/m2) and etoposide phosphate (150 mg/m2). This drug administration protocol mimics the regimen routinely used in brain tumor patients undergoing BBB disruption chemotherapy (1 , 15) . STS was given i.v. at a dose of 8 g/m2. The experimental conditions were: (1) no treatment (n = 20); (2) carboplatin + etoposide phosphate (n = 20); (3) carboplatin + etoposide, followed at 2 h and at 6 h with STS (n = 8); and (4) carboplatin + etoposide, followed in 8 h with STS (n = 8).
STS Pharmacology Studies.
Five male American shorthair outbred guinea pigs were anesthetized with
sodium pentobarbital (30 mg/kg) and given STS at a dose of 11.6
g/m2. STS was given as an i.p. bolus
(n = 2) or as a 15-min i.v. infusion in the femoral
vein (n = 3). Sixteen female Long Evans rats weighing
220–260 g were anesthetized with sodium pentobarbital (50 mg/kg) and
given STS at doses ranging from 6–11.6 g/m2. STS
was administered either i.p. (n = 6) or as a 15-min
i.v. infusion in the femoral vein (n = 10). Blood and
urine samples were collected immediately after the i.v. infusion, or at
15 min (guinea pigs and rats) or 30 min (rats) after the i.p. bolus
dose of STS.
Four dogs were given a 15-min infusion of 10% STS i.v. at rates that provided doses of 20 g/m2 (n = 2), 30 g/m2 (n = 1), or 40 g/m2 (n = 1). In the dogs, serum was collected for determination of STS concentrations, acid-base status, and sodium and potassium concentrations during the infusion, immediately after, and 30 min after infusion. Urine was collected between 5 and 20 min after STS infusion and assayed for STS. In one dog, CSF was collected 4 h after STS infusion and assayed for STS concentration. Additionally, continuous electrocardiograms (n = 4) and noninvasive blood pressure monitoring (n = 2) were performed in the dogs during and after the STS infusion. All blood, urine, and CSF samples were evaluated for STS concentration using the methylene blue method, as described by Ivankovich et al. (17) .
Carboplatin Pharmacokinetic Study.
Guinea pigs were given carboplatin (24 mg/kg), followed at 1 h by
furosemide (100 mg/kg), and followed at 2 h by either STS (11.6
g/m2, n = 3) or saline
(n = 3). Blood samples (0.5 ml each) were collected 5
min after each drug administration, as well as at 30 min, 1 h,
2 h, 3 h, 4 h, and 6 h after STS, with fluid
replacement at each withdrawal time point. Plasma was prepared by
centrifugation for 10 min at 3000 x g and 4°C and
was stored at -70°C until analyzed for both total and
ultrafilterable platinum. Ultrafiltrates were prepared using Amicon
Centrifree micropartition devices (Amicon Division, WR Grace, Beverly,
MA) with centrifugation at 2000 x g for 20 min at
4°C. Platinum concentration in plasma and ultrafiltrate was assessed
with a Perkin-Elmer model 1100 flameless atomic absorption spectrometer
(Perkin-Elmer Corp., Norwalk, CT) following a method validated in our
laboratory and described previously (18)
. This method is
similar to the platinum measurements described by Saito et
al. (19)
.
Guinea Pig Ototoxicity Study.
American shorthair outbred guinea pigs, weighing 400 g and having an
active Preyer pinna reflex, were used for the ototoxicity study
(n = 4). To allow i.v. infusion of experimental agents,
an indwelling polyethylene catheter (PE 50) was inserted into the left
external jugular vein of each animal. The animals were anesthetized
with pentobarbital (32 mg/kg i.p.), the surgical site was clipped of
hair and scrubbed with Betadine, and the surgery was performed using
sterile technique. After catheter placement, the surgical site was
closed with Michelle wound clips. All guinea pigs were given cisplatin
(6 mg/kg), followed after 1 h by furosemide (100 mg/kg). At 2 h after cisplatin, two animals were given STS (11.6
g/m2) and two were given saline. The i.v.
catheter was then removed, and the animals were returned to the animal
care quarters where they were maintained for 8 weeks to allow the drug
effects to stabilize.
Both ears of each animal were tested electrophysiologically, but only one ear from each saline animal was evaluated. Each guinea pig was anesthetized using i.p. allobarbital (60 mg/kg) and urethane (240 mg/kg). An endotracheal tube was inserted, and the animal was mechanically ventilated. Body temperature was maintained at 38.5°C, as monitored with a rectal thermistor probe. Scalp electrodes were placed to record ABR thresholds. For measurements of the compound action potential (N1) threshold, the middle ear was exposed and a small silver ball electrode was placed on the round window membrane, as previously reported (8) . ABR and N1 thresholds were determined at six different frequencies from 2 KHz through 32 KHz.
Data Analysis.
For the s.c. tumor growth study, tumor volume was determined
daily by caliper measurements, using the formula: volume =
width2 x length/2. The delay between tumor implantation
and the appearance of a measurable tumor, recorded as tumor day after
implantation, was determined for each treatment group. This time to
tumor progression was compared by one-way ANOVA using the JMP
statistical program (SAS Institute Inc, Cary, NC). Comparisons for all
pairs were made with Student’s t test using the
Tukey-Kramer procedure. The probability of appearance of measurable
s.c. tumors was also assessed nonparametrically by the product limit
(Kaplan-Meier) method, using the JMP statistical software. For STS
pharmacokinetic studies, blood and urine STS concentrations were
measured as described previously (8
, 17)
, and means and
SEs were determined for each species. In the carboplatin
pharmacokinetic study, serum total platinum was comparable with
ultrafilterable platinum concentrations for all animals and time
points, therefore, only ultrafilterable platinum values are presented.
Platinum concentration x time data for individual guinea pigs
were analyzed using noncompartmental methods. Area under the
concentration x time curve (AUC) was calculated with the log
trapezoidal method. Clearance of ultrafilterable platinum was
calculated from the equation: Clearance = dose/AUC. For the guinea
pig hearing studies, mean N1 thresholds and ABR
measurements were recorded and means and SDs were compared by
Student’s t test at each frequency, and with each ear
treated as an independent measurement.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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When animals were treated with carboplatin and etoposide phosphate
24 h after implantation of the tumor cells, a 60% increase was
observed in the time to tumor progression. The delay between tumor cell
inoculation and detection of a measurable tumor increased from 5.5 ± 0.4 days in the untreated control animals (n = 20),
to 8.9 ± 0.6 days in the chemotherapy animals (n = 18, P = < 0.001; Fig. 1A).
A product-limit
(Kaplan-Meier) plot of the results for s.c. tumor growth in the rat
model demonstrated that the carboplatin/etoposide treatment
significantly decreased the probability of detecting tumor growth at
early days after implantation (Fig. 1B).
Treatment with STS
at 2 h plus 6 h after carboplatin decreased the antitumor
effect of the chemotherapy (Fig. 1B,
Line 3). The
time delay to a measurable tumor was 6.4 ± 0.8 days
(n = 8) if animals received the two early boluses of
STS, which is significantly below the treatment with chemotherapy alone
(P = 0.012) and not significantly different from the
untreated tumor growth (P = 0.164). Delay of the STS
administration to 8 h after carboplatin/etoposide resolved much of
its negative interaction with the chemotherapy
Line 4). Administration of STS 8 h after the combined
carboplatin and etoposide phosphate treatment allowed significant
prolongation of time to tumor detection (8.1 ± 0.7 days,
n = 8, versus no treatment 5.5 ± 0.4
days, n = 20, P = 0.0023) and did not
significantly reduce the efficacy of the drug treatment compared with
chemotherapy alone (8.1 ± 0.7 d, n = 8,
compared with 8.9 ± 0.6 days, n = 18,
P = 0.188; Fig. 1A).
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. Serum STS concentrations in
guinea pigs and rats were assayed before and 15 min after an i.p. bolus
or after a 15-min infusion of STS. When assessing all animals,
regardless of route of administration, rats attained serum STS
concentrations of 504 ± 106 mg/dl (n = 5),
whereas guinea pig STS concentrations were 564 ± 70 mg/dl
(n = 5) after receiving 11.6 g/m2
of STS, as reported previously (8)
. STS was very rapidly
excreted by the kidneys, and high STS concentrations were documented in
the urine of all rats and guinea pigs, as reported previously
(8)
. No STS was detectable in the serum of these animals
before STS administration (n = 11). In both guinea pigs
and rats, serum STS values were more variable and generally lower if
measured 15 min after the i.p. bolus, as compared with immediately
after the 15-min i.v. infusion (Table 1)
. When rats given 6
g/m2 of STS were evaluated at 30 min after the
i.p. bolus, serum STS was increased to 144 ± 147 mg/dl
(n = 4), demonstrating slower uptake of STS via the
i.p. route. Doses of STS ranging from 6–8 g/m2
were used in the rat to achieve serum STS levels similar to those
attained in humans (330 mg/dl; Ref. 15
).
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. Mild to moderate hypernatremia (154–170 mEq/L) and mild
hypokalemia (2.26–3.46 mEq/L) occurred in all dogs and were more
pronounced with increasing STS dose. No STS was detected in the CSF of
the one dog tested at 4 h after STS infusion.
Effect of STS on Carboplatin Pharmacokinetics in the Guinea Pig.
The effect of STS on serum concentrations of platinum in the guinea pig
was analyzed to determine whether the chemoprotectant might bind to and
eliminate circulating carboplatin. Guinea pigs were given carboplatin
(24 mg/kg), followed 1 h later by furosemide (100 mg/kg), and
followed at 2 h by either STS (11.6 g/m2,
n = 3) or saline (n = 3), to mimic the
ototoxicity induction/protection regimen used in previous experiments.
Blood samples collected after each drug administration and throughout
the clearance period were evaluated for ultrafilterable and total
platinum concentration. The plasma concentration of ultrafilterable
platinum in guinea pigs with and without STS administration are shown
in Fig. 2
. No significant effect of STS
on ultrafilterable platinum concentration was found in these animals.
One animal showed a rapid drop in serum ultrafilterable platinum at the
point taken 5 min after the addition of STS, but serum platinum
returned to near pre-STS infusion levels by 30 min after infusion of
STS. Serum platinum concentrations were near zero by 8 h after
carboplatin administration, with or without STS addition (Fig. 2)
.
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. No difference
in clearance was found between animals given saline (184 ± 44
ml/hr/kg) compared with animals given STS (208 ± 51 ml/h/kg;
P = 0.33).
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. Animals treated with delayed
administration of STS maintained N1 thresholds
and auditory brainstem responses within the normal range throughout
this frequency range (Fig. 3)
. Both electrophysiological measures of
guinea pig hearing had equivalent results. Thus, STS prevented the
40–50 decibel increase in hearing threshold caused by cisplatin, even
when administered 2 h subsequent to the chemotherapeutic agent.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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In patients, the maximum tolerated dose of STS (20 g/m2) yields a serum STS concentration approximately equal to that achieved in the rats with 8 g/m2 (15) . A 4-h separation for bolus deliveries is tolerable in patients. Given these dosing and timing constraints, several possible timing regimen approaches are possible to delay the STS after the chemotherapy, including the two investigated in this study (a relatively short delay plus a long delay versus a very long delay). The more aggressive regimen (2+6 h STS) markedly reduced the efficacy of chemotherapy, making it inappropriate for otoprotection after platinum chemotherapy treatment. A single dose of STS administered with an 8-h delay did not impact tumor treatment, making it an exciting approach for patient treatment.
The possibility of reduced anticancer effect in the presence of chemoprotective agents is a major concern limiting their applicability (9) . Any reduction in chemotherapy concentration or activity may result in a decrease in the efficacy of the carboplatin or cisplatin. Results from other researchers are conflicting on this subject. Jones and Basinger (20) found no loss of cisplatin activity in rats treated with glutathione, used as a thioester in the same manner as STS. Iwamoto et al. (12) found that the addition of STS in two-route chemotherapy actually gave superior antitumor effects against mouse tumors. In contrast, Inoue et al. (21) found a decrease in the antitumor efficacy of cisplatin with the addition of STS. They found that administration of STS even 72 h after cisplatin significantly depressed cisplatin activity (21) . This contrasts with our study, which showed no significant loss of carboplatin activity when STS was administered 8 h after chemotherapy. The reasons for these differences are not known.
Potential for Chemoprotection against Ototoxicity.
Hearing loss is a serious side effect of chemotherapy with the platinum
drugs and can have a negative impact on the quality of life that
patients face after therapy. Ototoxicity is a major toxicity of
cisplatin and is also recognized as an increasing problem with
caboplatin therapy. Treatment protocols that increase the delivery of
carboplatin to the cochlea may be associated with increased incidence
of ototoxicity. For example, when carboplatin was delivered across the
BBB with osmotic BBB disruption for treatment of brain tumors,
high-frequency hearing loss was detected in 79% of patients (1
, 15)
. Additionally, sensitive populations, such as children, may
be more likely to suffer carboplatin ototoxicity. A recent study
assessed ototoxicity in children treated with standard-dose carboplatin
for neuroblastoma (7)
. Significant high-frequency hearing
loss was found, and only 2 of 11 patients had no ototoxicity
(7)
. In studies in which ototoxicity is not rigorously
screened with serial audiometric testing, self-reported or anecdotal
assessment of hearing loss may underestimate the problem of
high-frequency hearing loss.
The results described herein confirm and expand our results, indicating that STS dramatically reduced the level of auditory damage due to administration of platinum. Our previous work in the guinea pig model demonstrated that carboplatin-induced ototoxicity could be completely prevented by treatment with STS as late as 8 h after carboplatin (8) . In the current study, the protective effect of STS against platinum-induced hearing loss was documented in guinea pigs treated with cisplatin and furosemide. The previous results with carboplatin in the guinea pig model led us to test the potential for STS otoprotection in patients. We demonstrated a significant reduction in the magnitude of hearing loss after one treatment with carboplatin in patients receiving STS (3.7 ± 2 decibel, n = 15) in comparison with the historical comparison group (20.8 ± 5.9 decibel, n = 19; Ref. 15 ). The reduction of cisplatin ototoxicity by STS in the guinea pig model supports the possibility that STS may be effective against cisplatin in patients as well.
Several attempts have been made to reduce the toxicities of cisplatin
by using chemoprotective agents, although few of these studies targeted
ototoxicity. Amifostine (Ethyol, WR2721) has been evaluated clinically
as a chemoprotective agent with potential otoprotective activity
(22)
. However, whereas a decrease in peripheral
neurotoxicity was demonstrated, it is unclear whether otoprotection was
found. In one clinical study, grade 3 ototoxicity occurred in 3 of 25
patients given amifostine in conjunction with cisplatin therapy
(23)
, whereas in another study 3 of 13 patients with
metastatic breast carcinoma displayed ototoxicity with a similar
regimen (24)
. In the presence of another chemoprotective
agent, diethyldithiocarbamate, ototoxicity incidence remained at
50% and became the dose-limiting toxicity (25)
. The
amino acid D-methionine is a thiol-ether that has been
proposed for otoprotection against the platinum chemotherapeutics
(26
, 27)
. In animal models, D-methionine
effectively reduced the hearing loss caused by high-dose cisplatin
(26)
, but this agent has not yet been tested for
otoprotection in patients. In a preliminary study in the rodent LX-1
s.c. tumor model, we found that pretreatment with
D-methionine did not significantly reduce time to tumor
progression compared with chemotherapy with carboplatin plus etoposide
phosphate (7.8 ± 0.5 days, n = 8 compared with
8.9 ± 0.6 days, n = 18, P =
0.070).
Many of the previous studies using two-route chemotherapy with the combination of high-dose i.p. cisplatin and i.v. STS demonstrated that chemoprotection for nephrotoxicity necessitated the addition of STS either concurrently with cisplatin or within 5 min of the chemotherapy (12 , 13 , 14) . The 2- to 8-h timing for STS administration in the current study represents a significant delay. This timing difference (i.e., 8 h) may be key to reducing the undesirable ototoxic effects of carboplatin while maintaining a high therapeutic effect.
Mechanism of STS Rescue of Carboplatin Toxicity.
In vitro, STS binds directly to the electrophilic platinum,
producing an inactive complex (10
, 11)
. The molar ratio of
STS to platinum agent is a primary determinant of the extent and rate
of neutralization of platinum, and optimal ratios of STS have been
shown to be 400:1 for cisplatin and 40:1 for carboplatin (10
, 11)
. It is not clear whether this chemical neutralization is the
mechanism of STS chemoprotection in vivo.
In vivo, the deactivation of cisplatin or carboplatin will depend on both the concentration of STS achieved in the serum and its timing related to cisplatin or carboplatin. In our animal studies, i.v. administration of STS was superior, in confirmation of results by Iwamoto et al. (12) . In patients, serum STS levels could not be elevated as high as in the animals because of hypernatremia and hypertension, but the levels achieved were effective for otoprotection (15) . The high serum STS concentrations achieved in our animal studies did not seem to alter plasma ultrafilterable platinum pharmacokinetics. One caveat is that the ultrafilterable platinum likely includes platinum bound to STS, which could not be distinguished from ultrafilterable platinum that was not bound to STS by the atomic absorption assay used. The presence of STS-platinum conjugates could have reduced the amount of active drug available, although an alteration in platinum pharmacokinetics was not detected. This lack of effect of STS on serum platinum concentrations confirms findings by Saito et al. (19) using a similar platinum assay.
A delay between administration of platinum drug and the subsequent administration of STS makes use of the clearance of these drugs to reduce the concentration of free drug available to interact with STS. It would then be easier to attain a high molar ratio of STS to platinum for deactivation of both remaining free drug as well as drug bound to cellular targets. This would be especially beneficial in patients because lower maximum serum STS concentrations can be achieved (15) . When STS is administered at 8 h after carboplatin, a time point at which it remains otoprotective, we found that serum platinum concentrations were near zero. It, thus, seems unlikely that reducing the remaining free carboplatin concentrations can account for the chemoprotective effect of STS. Although the mechanism of STS otoprotection at the molecular level is unknown, we hypothesize that there is direct interaction with the hair cells of the cochlea, to rescue them from carboplatin that has already bound to cellular targets. For example, STS may reduce platinum-DNA adducts, or restore the activity of DNA repair enzymes (28) .
Potential Use of STS in the Clinical Setting.
Given the incidence of high-frequency hearing loss associated with
chemotherapy with the platinum agents, particularly cisplatin, a
mechanism to decrease ototoxicity could be important for maximizing
dosing and compliance and, therefore, chemotherapy efficacy. Delayed
administration of STS is currently under assessment in brain tumor
patients given enhanced delivery of carboplatin for treatment of
central nervous system tumors (15)
. We suggest that a
clinical trial to evaluate delayed administration of STS may be
warranted to extend the positive results achieved in brain tumor
patients, both children and adults, to systemic tumors being treated
with platinum chemotherapy.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Research support for this work was provided by a
VA merit review grant and by NIH Grants CA31770, NS34608, and
NS33618. 
2 To whom requests for reprints should be
addressed, at 3181 SW Sam Jackson Park Road, Portland, OR 97201. Phone:
(503) 494-5626; Fax: (503) 494-5627; E-mail neuwelte@ohsu.edu.
3 The abbreviations used are: BBB, blood-brain
barrier; ABR, auditory brainstem response; AUC, area under the curve;
CSF, cerebrospinal fluid; STS, sodium thiosulfate.
Received 8/13/99; revised 10/13/99; accepted 10/13/99.
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 N. D. Doolittle, C. P. Anderson, W. A. Bleyer, J. G. Cairncross, T. Cloughesy, S. L. Eck, P. Guastadisegni, W. A. Hall, L. L. Muldoon, S. J. Patel, et al. Importance of dose intensity in neurooncology clinical trials: Summary Report of the Sixth Annual Meeting of the Blood-Brain Barrier Disruption Consortium Neuro-oncol, January 1, 2001; 3(1): 46 - 54. [Abstract] [PDF]
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) or saline (
) at the time indicated
by the arrows. Blood samples were obtained at the
indicated times and analyzed for ultrafilterable platinum
concentration. Note that the 2-h sample was collected before STS and
the 2-h, 5-min sample was collected immediately after STS
administration. Each point indicates the mean ± SD for
n = 3 animals, except the sample obtained 5 min
after STS (*), which represents two STS samples and one saline
control.
and