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Ann Thorac Surg 1995;60:239-243
© 1995 The Society of Thoracic Surgeons

Original Articles: General Thoracic

Buthionine Sulfoximine Pretreatment Potentiates the Effect of Isolated Lung Perfusion With Doxorubicin

Jeffrey L. Port, MD, Steven N. Hochwald, MD, Hong-Yue Wang, MD, Michael E. Burt, MD, PhD

The Thoracic Oncology/Surgical Metabolism Laboratory, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York


   Abstract
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Introduction
 Material and Methods
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Background. Although surgical resection remains the mainstay of treatment for metastatic pulmonary sarcoma, 5-year survival approaches only 25%. Chemotherapy has been limited by tumor resistance and systemic toxicity. We assessed the efficacy of L-buthionine-SR-sulfoximine, an inhibitor of glutathione synthesis, as a sensitizer for isolated lung perfusion.

Methods. In experiment 1, sarcoma-bearing rats (n = 20) received either buthionine sulfoximine via intraperitoneal injection or Hespan. After the last injection, tumor glutathione levels were measured. In experiment 2, rats (n = 60) were injected with sarcoma intravenously. On day 6, animals were pretreated with either buthionine sulfoximine or Hespan intraperitoneally. On day 7, rats underwent isolated lung perfusion (Hespan or doxorubi-cin) or intravenous therapy (Hespan or doxorubicin). On day 14, tumor nodules were counted.

Results. Buthionine sulfoximine effectively depleted tumor glutathione. Animals treated with intravenous therapy had no response to therapy, whereas those animals treated with doxorubicin isolated lung perfusion alone had a limited response. Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion led to a 13-fold reduction in tumor nodules and 5 complete responses.

Conclusions. Buthionine-sulfoximine pretreatment in combination with doxorubicin isolated lung perfusion is superior to intravenous doxorubicin and doxorubicin isolated lung perfusion alone for the treatment of metastatic pulmonary sarcoma.


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See also page 244.

The management of metastatic pulmonary soft tissue sarcoma is a significant clinical problem. To date, standard systemic chemotherapy holds little promise for long-term survival [1]. Surgical resection remains the standard of care for metastatic pulmonary sarcoma, yet 5-year survival after complete resection approaches only 25% [1–4]. Treatment failures are usually local and stem from micrometastatic disease present at the time of resection [4], the high prevalence of sarcoma chemoresistance [5], and the toxicity of doxorubicin, which often precludes effective systemic chemotherapy [6]. Attempts have been made to increase the efficacy of antineoplastic therapy with locoregional delivery systems using high-dose chemotherapy [7–9]. This therapy produces increased local tissue levels with minimal systemic exposure. Other approaches have focused on selective, preferential tumor sensitization to chemotherapy, to reduce tumor resistance.

Glutathione may play a significant role in tumor resistance to chemotherapy and radiation [10, 11]. Buthionine sulfoximine (BSO) is a potent inhibitor of glutathione synthesis [10–14]. In this study, we have combined isolated doxorubicin lung perfusion with BSO for the treatment of pulmonary metastases. We hypothesize that the delivery of high-dose local chemotherapy in conjunction with glutathione depletion may potentiate tumor cytotoxicity while reducing unwanted systemic side effects.


   Material and Methods
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Animal Care
Animals (male Fischer F344 rats; Charles River, Kingston, NY) were treated in accordance with the Animal Welfare Act and the NIH ``Guide for the Care and Use of Laboratory Animals'' (NIH publication 85-23, revised 1985). Experiments were approved by the Institutional Animal Care and Use Committee of Memorial Sloan-Kettering Cancer Center. All rats were allowed access to standard laboratory rat chow (Purina Rat Chow; Ralston Purina, St. Louis, MO) and water ad libitum. Housing was temperature controlled and provided a 12-hour light/dark cycle.

Preparation of Tumor Cells
The tumor is a methylcholanthrene-induced sarcoma that has been serially passed subcutaneously in the flank of F344 rats and is well characterized. The tumor cells were harvested fresh from a tumor-bearing animal, and a single cell suspension prepared on the day of injection. The tumor is characterized by rapid growth and local invasion after subcutaneous implantation. Pulmonary metastases are induced in a reproducible fashion after intravenous injection.

Isolated Lung Perfusion
Isolated left lung perfusion was performed by the method previously established in this laboratory [7]. Animals were anesthetized with pentobarbital (50 mg/kg) intraperitoneally. Under direct visualization the animals were intubated with a 16-gauge intravenous catheter placed over a guidewire [15] and then placed on a volume ventilator (Rodent Ventilator model 683; Harvard Apparatus, South Natick, MA). Ventilation was maintained at a tidal volume of 10 mL/kg, with 100% O2 supplemented with 0.5% halothane at a rate of 75 strokes/min. The left side of the chest was shaved and prepared with a povidone-iodine 10% solution, and then entered through a fourth intercostal incision. The left pulmonary artery and vein were visualized under an operative microscope (OpMi-1,16x; Carl Zeiss, Wotan, Germany). A PE-10 catheter (Becton Dickinson & Co, Parsippany, NJ) was inserted into the pulmonary artery for infusion. A pulmonary venotomy was performed and the effluent suction collected by a catheter placed in proximity to the venotomy. At the completion of the perfusions both the venotomy and arteriotomy were repaired with 9-0 nylon suture (Ethicon, Somerville, NJ) and the pulmonary circulation was restored. Through a separate puncture wound, a 16-gauge catheter connected to a 3-mL syringe (Becton Dickinson & Co) was introduced into the left chest cavity to facilitate lung reexpansion. The thoracotomy incision was closed in three layers. When animals recovered, their chest tubes and endotracheal tubes were removed.

Experiment 1: BSO Dose Response
Twenty male F344 rats (250 to 300 g) were randomized into five groups (n = 4/group) to determine the appropriate dose of L-buthionine-SR-sulfoximine (Schweizerhall Inc, Plainfield, NJ) to be used for therapeutic studies. All animals were injected subcutaneously in the right flank with 1 x 107 viable methylcholanthrene-induced sarcoma cells. When the tumors reached approximately 5% tumor burden by weight, a dose response was performed to determine the dose of BSO that maximally decreased tissue glutathione levels. Animals underwent intraperitoneal injections (2 mL/injection) every 8 hours for 24 hours. Animals were randomized into the following five treatment groups: control (Hespan), group I (0.5 mmol/kg of BSO), group II (2.0 mmol/kg of BSO), group III (4.0 mmol/kg of BSO), and group IV (6.0 mmol/kg of BSO). Two hours after the last injection, animals were euthanized and tissues were harvested.

Experiment 2: Efficacy
Sixty male F344 rats (200 to 250 g) were randomized into six groups. On day zero, all groups underwent an intravenous injection of 5 x 106 viable methylcholanthrene-induced sarcoma cells via the right external jugular vein. On day 6 after inoculation, rats received pretreatment consisting of an intraperitoneal (IP) injection (2 mL/injection) of Hespan or BSO (2 mmol/kg) every 8 hours for three doses. Two hours after the last IP dose animals were treated with isolated lung perfusion (ILP) (doxorubicin or Hespan) or intravenous injection (doxorubicin or Hespan). Pretreatment and treatment for all groups were as follows: group I (n = 6) received Hespan IP and Hespan intravenously; group II (n = 6) received BSO IP and doxorubicin intravenously (25 µg in 0.5 mL); group III (n = 12) received Hespan IP and Hespan ILP; group IV (n = 12) received BSO IP and Hespan ILP; group V (n = 12) received Hespan IP and doxorubicin ILP; and group VI (n = 12) received BSO IP and doxorubicin ILP. Those groups that underwent ILP were perfused either with doxorubicin (10 µg/mL) for 5 minutes followed by a 2.5-minute Hespan washout or with Hespan ILP alone for 7.5 minutes at a rate of 0.5 mL/min (Syringe Infusepump 22; Harvard Apparatus). Those animals that underwent intravenous therapy were injected through their right jugular vein with either doxorubicin (25 µg in 0.5 mL) or 0.5 mL of Hespan. On day 14 after inoculation, all groups were euthanized and their left lungs were stained with India ink for identification of pulmonary metastases [16].

Glutathione Processing and Analysis
The tumors were excised, weighed, and immediately homogenized (Brinkmann Instruments, Westbury, NY) in 5% 5-sulfosalicylic acid (Fisher Scientific). A laparotomy was performed and the portal vein was cannulated with a 22-gauge angiography catheter. The liver was perfused with 10 mL of ice-cold saline solution to wash out red blood cells. A segment of the right lobe then was excised, weighed, and homogenized in 5% 5-sulfosalicylic acid. Samples were spun in a microfuge centrifuge (Fisher Scientific), and the supernatant was derivatized according to a modification of the method of Newton and associates [17].

One hundred twenty microliters of 2 mmol/L diethylenetriamine pentaacetic acid (Sigma) was added to 360 µL of sample. One hundred microliters of 2 mol/L Tris-HCl (pH 9) then was added, followed immediately by 5 µL of 0.1 mol/L monobromobimane (Calbiochem, LaJolla, CA). The reaction was allowed to proceed in the dark for 20 minutes and then was stopped with 15 µL of glacial acetic acid. Samples were quantitated by high-performance liquid chromatography (Waters Associates, Milford, MA) using fluorescence detection. The system consisted of a pump series 501, gradient controller 680, data module 746, and fluorescence detector 420-AC. One hundred microliters of the sample was injected into a 5-µm C18 (4.6 x 250 mm) Ultrasphere ODS (Beckman) column using a dual solvent system. Solvent A consisted of 9% methanol and 0.25% acetic acid (pH 3.9), and solvent B consisted of 90% methanol and 0.25% glacial acetic acid (pH 3.9). One hundred percent solvent A was run for 12 minutes at 1 mL/min., followed by 94% solvent A and 6% solvent B for 12 minutes. Then 100% solvent B was run for 25 minutes followed by reequilibration with solvent A. Curves were compared with external standards of glutathione (Sigma) derivitized in a similar fashion.

Chemicals
All chemicals were of high purity (high-performance liquid chromatography grade).

Statistical Analysis
All data are presented as mean +/- standard deviation. Analysis was performed by one-way analysis of variance or unpaired t test where appropriate. Significance was defined as p less than or equal to 0.05.


   Results
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 Introduction
 Material and Methods
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Comment
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Experiment 1: Dose Response
The body weights and percent tumor burden by weight were similar between groups. Body weights of the control group were 280 +/- 13 g, and for groups I through IV were 277 +/- 21, 274 +/- 17, 277 +/- 14, and 279 +/- 18 g, respectively (p = not significant). The percent tumor burden in all groups ranged from 2% to 4% (p = not significant). Buthionine-sulfoximine treatment decreased liver and tumor glutathione levels in a dose-dependent manner (Figs 1, 2GoGo). Liver glutathione level for the control group was 20.60 +/- 0.60 µmol/g, and for groups I through IV the levels were 8.60 +/- 4.24, 2.31 +/- 0.23, 1.62 +/- 0.54, and 1.90 +/- 1.35 µmol/g, respectively. Liver glutathione levels in rats that received BSO (groups I through IV) were significantly decreased in comparison with the control group (p <= 0.05). In addition, liver glutathione levels were further decreased in groups II through IV when compared with group I (p <= 0.05). Tumor glutathione level in the control group was 2.26 +/- 0.07 µmol/g, and the levels in groups I through IV were 0.39 +/- 0.12, 0.28 +/- 0.09, 0.21 +/- 0.10, and 0.16 +/- 0.03 µmol/g, respectively. Tumor glutathione levels in groups I through IV were decreased in comparison with the control group (p< 0.05). In addition, tumor glutathione levels were decreased further in groups III and IV in comparison with groups I and II (p <= 0.05).



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  		Fig 1. . Liver glutathione levels after treatment with buthionine sulfoximine (BSO) (n = 4 rats/group; dose: group I, 0.5 mmol/kg; group II, 2.0 mmol/kg; group III, 4.0 mmol/kg; group IV, 6.0 mmol/kg). (ap < 0.05 versus CTL; bp < 0.05 versus group I; CTL = control group.)

 


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  		Fig 2. . Tumor glutathione levels after treatment with buthionine sulfoximine (BSO) (n = 4 rats/group; dose: group I, 0.5 mmol/kg; group II, 2.0 mmol/kg; group III, 4.0 mmol/kg; group IV, 6.0 mmol/kg). (ap < 0.05 versus CTL; bp < 0.05 versus group I; CTL = control group.)

 
Experiment 2: Efficacy
There was no immediate perioperative mortality in any of the groups. Two animals in group III died on day 13 after inoculation with massive, bilateral, pulmonary tumor replacement. Treatment response is depicted in Table 1Go. There was no difference in treatment-related mortality among the groups. All groups had massive tumor replacement of their untreated right lungs (Fig 3Go). There was no response to treatment noted in the left lungs of those animals that received either Hespan or doxorubicin intravenous therapy (groups I and II) or Hespan ILP (groups III and IV). Those animals that received doxorubicin ILP (groups V and VI) had a decrease in the number of tumor nodules in their treated left lungs in comparison with groups I to IV (p <= 0.01). There was a substantial difference in response between groups V and VI as well. There were 223 +/- 97 nodules in the treated left lungs of animals that received Hespan pretreatment with doxorubicin ILP (group V) and 16 +/- 22 nodules in the treated left lungs of animals that received pretreatment with BSO and doxorubicin ILP (group VI; p <= 0.01). In addition, there was a complete response to therapy in 5 of the animals in group VI with no complete responses in group V.


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  		Table 1. . Response to Therapy
 


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  		Fig 3. . A single, representative, posterior view of the lungs of the four treatment groups that underwent isolated lung perfusion (ILP): (A) Hespan intraperitoneally/Hespan ILP (group III), (B) BSO intraperitoneally/Hespan ILP (group IV), (C) Hespan intraperitoneally/doxorubicin ILP (group V), (D) BSO intraperitoneally/doxorubicin ILP (group VI).

 

   Comment
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Soft tissue sarcomas metastasize almost exclusively to the lung, and the lung is often the sole site of recurrence after treatment [18]. Although surgery remains the mainstay of treatment for metastatic pulmonary sarcoma, 5-year survival after complete resection only approaches 25% [1]. Residual microscopic pulmonary disease is thought to be responsible for local recurrence after complete resection [4]. Combination chemotherapy has been implemented to treat metastatic pulmonary sarcoma [1]. Doxorubicin-based regimens have proved to be the most efficacious [6]. However, doxorubicin-associated cardiac toxicity [6] and the frequent development of drug-resistant tumor cell populations after repeated courses of doxorubicin have limited the systemic use of this drug [19]. Attempts have been made to potentiate the cytotoxic effects of chemotherapy while minimizing systemic toxicity. Ideally, a strategy is needed that would produce preferential sensitization of tumor cells while providing simultaneous protection of normal tissue.

To address the clinical problem of systemic toxicity of chemotherapy, we have developed a technique of ILP with doxorubicin in the rat that results in minimal systemic drug toxicity, operative morbidity, and mortality [7]. With this model, we are capable of raising pulmonary levels of doxorubicin to 20 times that of comparable systemic doses with a sevenfold reduction in heart concentrations. Although this technique holds the promise of delivering high-dose local chemotherapy without adverse systemic exposure, there is still a real concern regarding local toxicity. Studies examining isolated doxorubicin lung perfusion in dogs noted significant lung damage at low drug concentrations [8]. The ability to increase doxorubicin tumor cytotoxicity at lower concentrations might further reduce the toxicity to surrounding normal tissue.

The acquired resistance of cancer cells to antitumor drug therapy is frequently a major cause of treatment failure in patients [19]. Chemotherapy is administered routinely at near maximum tolerated doses. It is usually not possible to increase the dose of an agent by even twofold [5]. Therefore, the degree of drug resistance necessary for a tumor to become refractory to conventional therapy is minimal.

The mechanism by which tumor cells develop resistance to antineoplastic therapy has been the focus of considerable research efforts. The ability to overcome this resistance offers the potential for increased chemotherapeutic efficacy at lower tissue levels and with less systemic toxicity.

A number of mechanisms have been proposed to explain tumor drug resistance. There is increasing evidence to support a pivotal role for glutathione in the resistance of tumors to chemotherapy and radiation [10–14]. Glutathione is the major component of the intracellular nonprotein sulfhydryl pool, and acts as a detoxifying agent by scavenging free radicals. Glutathione has been shown to be important in the detoxification of chemotherapeutic agents such as doxorubicin that produce activated oxygen species such as hydrogen peroxide, superoxide, and hydroxyl groups [20, 21]. The recent discovery of chemoresistant human tumor cells that contain higher levels of glutathione and glutathione synthetic activity in comparison with chemosensitive tumor cells as well as normal cells suggests that glutathione may be an important factor capable of providing tumor resistance to conventional cancer treatment [22]. Pharmacologic manipulation of tissue glutathione levels may allow augmentation of antineoplastic therapy. Buthionine sulfoximine is a potent inhibitor of {gamma}-glutamylcysteine synthetase, an enzyme catalyzing the rate-limiting step in glutathione synthesis [9–13]. Buthionine sulfoximine has been shown to increase the effectiveness of numerous chemotherapeutic agents in vitro and in vivo [10–14]. It was found that BSO pretreatment of mice bearing drug-resistant leukemia cells before chemotherapy led to an increased survival [11]. A relationship between ovarian cancer drug resistance and glutathione activity has also been established [14]. This resistance has been shown to be reversed by BSO depletion of tumor cell glutathione levels. It is therefore possible that the clinical use of BSO in combination with chemotherapy might provide a means of overcoming drug resistance in tumors. However, the administration of BSO might sensitize normal tissue to systemic chemotherapy and increase unwanted toxicities. Ideally, a system that delivered locoregional chemotherapy without systemic leak could capitalize on BSO pretreatment and tumor sensitization without increasing systemic toxicity. This study examined the effect of the addition of BSO pretreatment in conjunction with doxorubicin ILP for the treatment of metastatic pulmonary sarcoma. The first experiment was performed to determine the appropriate dose of BSO pretreatment in our animal model. Other studies previously have examined the pharmacokinetics of BSO treatment and have demonstrated a substantial reduction in tissue glutathione level lasting several days after a similar BSO dosing regimen [11, 13]. We anticipated that if glutathione did play a significant role in methylcholanthrene-induced sarcoma drug resistance, that short-term glutathione depletion would be adequate to demonstrate increased efficacy with ILP. Pretreatment of animals with 2 mmol/kg (x 3 doses) of BSO over 24 hours depleted liver and tumor glutathione levels maximally. This dose then was used to determine if BSO pretreatment would increase the efficacy of doxorubicin ILP.

There were no differences in mortality among the groups. This indicates that BSO pretreatment can be administered safely in conjunction with ILP. In addition, this combined treatment modality was highly effective for the treatment of metastatic pulmonary sarcoma. There was a 13-fold reduction in tumor nodules in 7 animals and a complete response in 5 animals that were pretreated with BSO followed by doxorubicin ILP in comparison with all other therapies. The group pretreated with Hespan followed by doxorubicin ILP had only a limited response to therapy with no complete responses. No other groups had a response to therapy. These experiments indicate that BSO pretreatment potentiates the efficacy of doxorubicin delivered by ILP.

In summary, 2 mmol/kg of BSO IP given in three doses over 24 hours is effective in depleting tumor glutathione levels in our model. Using this dose of BSO, we have demonstrated that ILP with doxorubicin combined with BSO pretreatment is superior therapeutically to doxorubicin ILP alone or to intravenous doxorubicin with BSO pretreatment. Isolated lung perfusion with BSO pretreatment offers the potential for a selective increase in tumor sensitization and cytoxicity with minimal systemic exposure. In addition, these benefits may be achieved at lower doses of chemotherapy, which potentially would reduce local toxicity to normal tissue. In conclusion, the addition of BSO pretreatment may prove useful for future clinical studies examining the efficacy of ILP for the treatment of metastatic pulmonary disease.


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Presented at the Thirty-first Annual Meeting of The Society of Thoracic Surgeons, Palm Springs, CA, Jan 30--Feb 1, 1995.

Address reprint requests to Dr Burt, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021.


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  1. Lanza LA, Putnam JB, Benjamin RS, Roth JA. Response to chemotherapy does not predict survival after resection of sarcomatous pulmonary metastases. Ann Thorac Surg 1991;51:219–24.[Abstract]
  2. Jablons D, Steinberg SM, Roth JA, et al. Metastectomy for soft tissue sarcoma. J Thorac Cardiovasc Surg 1989;97:695–705.[Abstract]
  3. Casson AG, Putnam JB, Natarajan G, et al. Five-year survival after pulmonary metastectomy for adult soft tissue sarcoma. Cancer 1992;69:662–8.[Medline]
  4. Huth JF, Holmes EC, Vernon SE, et al. Pulmonary resection for metastatic sarcoma. Am J Surg 1980;140:9–14.[Medline]
  5. Samuels BL, Murray JL, Cohen MB, et al. Increased glutathione peroxidase activity in a human sarcoma cell line with inherent doxorubicin resistance. Cancer Res 1991;51:521–7.[Abstract/Free Full Text]
  6. Casper ES, Gaynor JJ, Hajdu SI, et al. A prospective randomized trial of adjuvant chemotherapy with bolus versus continuous infusion of doxorubicin in patients with high grade extremity soft tissue sarcoma and an analysis of prognostic factors. Cancer 1991;68:1221–9.[Medline]
  7. Weksler B, Ng B, Lenert JT, Burt M. Isolated single-lung perfusion with doxorubicin is pharmacokinetically superior to intravenous injection. Ann Thorac Surg 1993;56:209–14.[Abstract]
  8. Baciewicz FA, Arredondo M, Chaudhuri B, et al. Pharmacokinetics and toxicity of isolated perfusion of lung with doxorubicin. J Surg Res 1991;50:124–8.[Medline]
  9. Johnston MR, Christensen CW, Minchin RF, et al. Isolated total lung perfusion as a means to deliver organ-specific chemotherapy: long term studies in animals. Surgery 1985;98:35–44.[Medline]
  10. Mitchell JB, Cook JA, DeGraff W, Glastein E, Russo A. Glutathione modulation in cancer treatment: will it work? Int J Radiat Oncol Biol Phys 1989;16:1289–95.[Medline]
  11. Meister A. Glutathione deficiency produced by inhibition of its synthesis, and its reversal: applications in research and therapy. Pharmacol Ther 1991;51:155–94.[Medline]
  12. Russo A, DeGraff W, Friedman N, Mitchell J. Selective modulation of glutathione levels in human normal versus tumor cells and subsequent differential response to chemotherapy drugs. Cancer Res 1986;46:2845–8.[Abstract/Free Full Text]
  13. Terradez P, Asensi M, De La Vega C, et al. Depletion of glutathione in vivo by buthionine sulfoximine: modulation by the rate of cellular proliferation and inhibition of cancer growth. Biochem J 1993;292:477–83.
  14. Ozols RF, Louie KG, Plowman J, et al. Enhanced melphalan cytotoxicity in human ovarian cancer in vitro and in tumor bearing nude mice by buthionine sulfoximine depletion of glutathione. Biochem Pharmacol 1987;36:147–53.[Medline]
  15. Weksler B, Ng B, Lenert JT, Burt M. A simplified method for endotracheal intubation in the rat. J Appl Physiol 1994;76:1823–5.[Abstract/Free Full Text]
  16. Wexler H. Accurate identification of experimental pulmonary metastasis. J Natl Cancer Inst 1966;36:641–5.
  17. Newton GL, Dorian R, Fahey RC. Analysis of biological thiols: derivitization with monobromobimane and separation by reverse-phase high-performance liquid chromatography. Anal Biochem 1981;114:383–7.[Medline]
  18. Potter DA, Glenn J, Kinsella T, et al. Patterns of recurrence in patients with high-grade soft-tissue sarcomas. J Clin Oncol 1985;3:353–66.[Abstract]
  19. Dusre L, Mimnaugh G, Myers CE, Sinha BK. Potentiation of doxorubicin cytotoxicity by buthionine sulfoximine in multidrug-resistant human breast tumor cells. Cancer Res 1989;49:511–5.[Abstract/Free Full Text]
  20. Meijer C, Mulder NH, Bosscha HT, Zijlstra JG, de Vries EG. Role of free radicals in an Adriamycin resistant human small cell lung cancer cell line. Cancer Res 1987;47:4613–7.[Abstract/Free Full Text]
  21. Meijer C, Mulder NH, de Vries EG. The role of detoxifying systems in resistance of tumor cells to cisplatin and Adriamycin. Cancer Treat Rev 1990;17:389–407.[Medline]
  22. Godwin A, Meister A, O'Dwyer P, et al. High resistance to cisplatin in human ovarian cancer cell lines is associated with marked increase of glutathione synthesis. Proc Natl Acad Sci USA 1992;89:3070–4.[Abstract/Free Full Text]

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