The role of glutathione in determining the response of normal and tumor cells to anticancer drugs.
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Animals↗
Biomedical subjects
J Carmichael
Publications and source records attributed to J Carmichael.
High-dose-intensity regimen of weekly doxorubicin and cisplatin in the treatment of patients with stage III and IV epithelial ovarian carcinoma.
Thirty-seven eligible patients with stage III or IV epithelial ovarian carcinoma were treated with weekly doxorubicin and weekly escalating cisplatin in an attempt to improve outcome by increasing the dose intensity of chemotherapy as compared to more conventional regimens given every 3-4 weeks. There was a 63% clinical response rate, with a median survival time of 18 months. Six patients (16.2%) had a complete surgical/histologic response (negative second-look laparotomy). Two patients had treatment-related deaths, and severe toxicity was responsible for four other patients having to discontinue treatment prematurely. The toxicity of this regimen jeopardized received (as opposed to projected) dose intensity and the regimen therefore offered no improvement compared to other drug combinations and schedules.
Adolescent↗
Adult neuroblastoma. Report of three cases and review of the literature.
Adult neuroblastoma is an uncommon malignancy. The authors report three additional cases and review the 39 reported cases in the world literature. Presentation in the abdomen is the most common; a high rate of lower limb presentation is also observed. Incidence is equal between sexes with median age of presentation of 34 years. Survival is greatest after surgical intervention (median, 20.5 months) compared with no surgery (median, 12.5 months). Chemotherapy may benefit individual patients but does not have a major impact on survival. Radiotherapy is indicated for localized, inoperable primaries or painful metastases. The survival rates of this group of patients parallels that of childhood neuroblastoma, Stage III-IV.
Adult↗
The roles of intracellular glutathione in antineoplastic chemotherapy.
Glutathione is a sulfhydryl containing tripeptide that participates in detoxification of xenobiotic compounds, including the alkylating agents melphalan, cyclophosphamide, and BCNU. The role of glutathione in the detoxification of these compounds, both in terms of initial tumor response, and drug-induced resistance to these alkylating agents is examined. Since glutathione disulfide and glutathione are a pivotal redox pair, the modulation of intracellular glutathione levels is shown to change the cytotoxicity of drugs dependent on the redox cycle, such as adriamycin and bleomycin, as well as the oxygen dependent drug neocarzinostatin. Areas of further research are discussed.
Animals↗
The relationship of SR-2508 sensitizer enhancement ratio to cellular glutathione levels in human tumor cell lines.
We have recently demonstrated that intracellular elevation of glutathione (GSH) by oxothiazolidine 4-carboxylate lessens SR-2508 hypoxic cell radiosensitization in Chinese hamster cells. This observation, coupled with the fact that GSH depletion potentiates SR-2508 hypoxic radiosensitization, prompted a study of human tumor cell lines whose inherent GSH levels are high compared to normal human cell lines or rodent cell lines. Sensitizer enhancement ratios (SER) for a range of SR-2508 concentrations were determined for human tumor cell lines varying in inherent GSH levels. The SER (at the 1% survival level) for 1 mM SR-2508 was found to decrease as the inherent intracellular GSH level increased, particularly for clinically relevant SR-2508 concentrations. All human tumor cell lines studied yielded lower SER values than Chinese hamster V79 cells over the SR-2508 concentrations studied. GSH depletion by buthionine sulfoximine (BSO) of a human tumor line (A549) particularly high in GSH resulted in potentiation of SR-2508 effects. Maximal sensitization occurred when extremely low GSH levels were attained; however, enhancement was observed for a drop of only 30% in GSH levels. Should these high GSH levels seen in human tumor cell lines also apply to clonogenic or potentially clonogenic cells in human tumors in vivo, these findings might explain, in part, the negative results of some human nitroimidazole clinical trials.
Cell Line↗
In vivo modulation of glutathione by buthionine sulfoximine: effect on marrow response to melphalan.
The effect of giving buthionine sulfoximine (BSO), 0.0265 g/mouse (6 mM), at 12 and 6 hr before treatment with melphalan--0.0 mg, 3 mg, 6 mg, and 9 mg/kg, was studied in C3H mice, and was compared with control groups that received normal saline 12 and 6 hr before identical melphalan treatment. BSO treatment resulted in depletion of GSH levels in bone marrow, liver, and muscle to 65, 13, and 41% of control levels, respectively. Hematological toxicity was assessed by measurement of CFU-S survival and peripheral white cell counts. CFU-S survival decreased with increasing doses of melphalan, but no difference was observed with BSO pre-treatment. Likewise, WBC counts following melphalan 9 mg/kg, were similar irrespective of BSO pre-treatment. These data suggest that the marrow toxicity seen with melphalan is not worsened by pre-treatment with BSO and that if tumors can be pre-sensitized with BSO, there may be a clinical role for melphalan/BSO drug combination.
Animals↗
Inhibition of the protective effect of cyclophosphamide by pre-treatment with buthionine sulfoximine.
Low dose cyclophosphamide (CTX) is protective against a subsequent challenge with a lethal dose of the same drug administered 5 days later. At the time of maximal protection, elevation of glutathione (GSH) and glutathione transferase (GST) levels are detectable in the bone marrow of pre-treated animals. Elevation of GSH levels in the bone marrow was inhibited with the use of D,L-buthionine-S,R-sulfoximine (BSO), and this resulted in loss of the protective effect of CTX pre-treatment. In contrast, the overshoot in GST levels observed in these animals was not affected by BSO therapy. Bone marrow GSH levels in animals treated with BSO alone were minimally depleted (68% of control); whereas, animals pre-treated with CTX followed by BSO exhibited a greater reduction in GSH levels (47% of control). These results suggest that GSH is important in the protective effect afforded by low dose CTX pre-treatment and that the elevation of GSH levels observed is the result of a rebound synthetic process. In CTX pre-treated animals, BSO treatment resulted in greater than predicted depletion in GSH levels, and, therefore, caution is recommended with the potential use of combinations of BSO and cytotoxic drugs in the presence of a regenerating bone marrow.
Animals↗
Human tumour xenografts growing in immunodeficient mice: a useful model for assessing chemotherapeutic agents in bronchial carcinoma.
Xenografts from eight human bronchial carcinomas have been established in CBA/Lac mice rendered immunodeficient by neonatal thymectomy followed three weeks later by whole body irradiation (7.35 Gy (735 rads)) after a priming dose of cytosine arabinoside. Growth rates of individual tumour lines remain constant and the histological and chromosomal characteristics of the original tumour are maintained through multiple serial passages over many months. With specific growth delay as the principal end point this system may be used to assess the response of histologically different lung tumours to chemotherapeutic agents.
Animals↗
Augmentation of cytotoxicity of chemotherapy by human alpha-interferons in human non-small cell lung cancer xenografts.
Three human non-small lung cancer xenograft lines were used to study the activity of combinations of cytotoxic drugs with human alpha-interferons (IFNs). Statistically significant potentiation of cis-platinum (CDDP) and cyclophosphamide (CY) given weekly in a low dose was seen when human lymphoblastoid interferon (IFN-alpha nl) (2 X 10(5) mu/mouse/day) was administered simultaneously. The median tumor doubling times for CDDP in the three tumors (35, 22, and 29 days) increased to 52, 51, and 41 days when IFN-alpha nl was added. A similar though less marked effect was seen with CY (median doubling time increased from 21.5, 19.5, and 27 days to 32, 27, and 35 days with the addition of IFN-alpha nl). IFN-alpha nl alone at this dosage was shown to have some cytotoxic activity. Similar potentiation of CDDP and ifosfamide was seen in two tumors when human recombinant alpha-2 interferon was added at a lower dose (2 X 10(4) mu/mouse/day). Median doubling times for CDDP increased from 17 and 14 days to 27 and 18.5 days with the addition of human recombinant alpha-2 interferon, whereas for ifosfamide they increased from 11.5 and 14 days to 15 and 16 days. Human recombinant alpha-2 interferon in this dose had no effect as a single agent.
Animals↗
Glutathione and glutathione transferase levels in mouse granulocytes following cyclophosphamide administration.
Following an initial depletion, glutathione and glutathione transferase levels are transiently increased in mouse bone marrow following the administration of a low dose of cyclophosphamide. Similar effects are observed on subsequent administration of the drug. The separation of various bone marrow populations on a fluorescence-activated cell sorter has shown that increase in glutathione and glutathione transferase levels are restricted to the granulocytic fraction. This may well provide an explanation for the protective effect of a low 'priming' dose of cyclophosphamide against a subsequent lethal dose. The changes in granulocytic glutathione and glutathione transferase levels can also be monitored in the peripheral circulation. The enhanced levels of glutathione in cells resulting from cytotoxic insult appear to be a general response of cells to cytotoxins and may be important in both antitumor therapy as well as the initiation of chemical toxicity and carcinogenicity.
Animals↗
Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function.
In the past 15 years, there has been an explosion in the number of nonsteroidal anti-inflammatory drugs on the market. Along with this explosion have come increasing reports of the physiologic and pathologic changes seen in the kidneys. This report reviews the effects of prostaglandins on the kidney and the physiologic changes that result when prostaglandin synthesis is blocked. The world literature on renal complications of nonsteroidal anti-inflammatory drugs is reviewed and 274 cases of acute renal disease associated with their use are reported. The following cases are described: nephrotic syndrome (34); acute interstitial nephritis (51); acute tubular necrosis (29); papillary necrosis (53); poor perfusion with renal failure (40); acute glomerulitis or vasculitis (13); and unspecified renal failure (102). Fenoprofen appeared to be more nephrotoxic than other nonsteroidal anti-inflammatory drugs and resulted in multiple renal lesions in the same patient.
Anti-Inflammatory Agents↗
cis-Platinum and vindesine in combination in the treatment of non-small cell lung cancer.
Sixty-three patients with advanced non-small cell carcinoma of the bronchus were treated with a combination of cis-platinum and vindesine. All patients had measurable disease and were of good performance status; none had received prior chemotherapy or radiotherapy. Thirty-three per cent of patients responded, with five patients achieving complete remission. Median duration of response was 4 months, with a median survival of 14 months in the responsers, compared with 6.5 months in the whole group and 4.8 months in the nonresponders. Severe toxicity was encountered, with alopecia, gastrointestinal toxicity and neurotoxicity common. Myelosuppression and renal toxicity were not dose-limiting. Thus the activity of this drug combination is confirmed, but severe toxicity precludes its widespread use in clinical practice.
Adenocarcinoma↗
Medical recommendations for wilderness travel. 1. Health maintenance in the great outdoors.
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Altitude Sickness↗
Medical recommendations for wilderness travel. 2. Field management of illness and injury.
Knowledge of basic treatment of several illnesses and injuries common in wilderness travel can save time and discomfort on the trail. In some cases evacuation and medical attention will be necessary, but proper initial measures can be crucial to a successful outcome.
Altitude Sickness↗
Medical recommendations for wilderness travel. 3. Medical supplies and drug regimens.
Even if the wilderness traveler is fit and up-to-date on management of the many illnesses and injuries that may occur on an outing, proper care cannot be given unless the appropriate supplies are available. Thus, the contents of a medical travel kit should be carefully chosen, using the type of trip, duration of travel, and distance from medical care as criteria.
Anti-Bacterial Agents↗
Cis-platin and methotrexate in the treatment of transitional cell carcinoma of the urinary tract.
Nineteen patients with recurrent or metastatic transitional cell carcinoma of the urinary tract were treated with a 3-weekly combination of methotrexate 200 mg/m2 as a 24-h infusion with folinic acid rescue and cis-platin 100 mg/m2. An objective response rate of 68% was obtained, with 4 patients (21%) achieving complete remission. Pulmonary disease and lymph node metastases were particularly sensitive to this therapy. The median duration of response was 21 weeks with a median survival of 54 weeks in the responding patients. This regimen warrants further investigation in the treatment of invasive bladder carcinoma.
Aged↗
Altered mouse bone marrow glutathione and glutathione transferase levels in response to cytotoxins.
The mouse bone marrow has been used as a model for the investigation of the response of cells to cytotoxins and carcinogens. The effects of cyclophosphamide, 1-beta-D-arabinofuranosylcytosine, and X-irradiation on the levels of glutathione and glutathione transferases have been studied. A high dose of cyclophosphamide (500 mg/kg) caused a significant depletion of glutathione levels in marrow, liver, and blood. A lower dose, 75 mg/kg, caused a similar depletion but only in marrow and liver. In this case, 5 to 7 days following treatment, the glutathione content of surviving cells was 1.8- to 3-fold higher than in controls. Glutathione transferase activity was also increased at this time (2- to 3-fold). 1-beta-D-Arabinofuranosylcytosine and X-irradiation also caused a depletion of marrow glutathione and glutathione transferase levels followed increased cellular levels (approximately 2-fold) 3 to 4 days later. Animals given cyclophosphamide (75 mg/kg) survived an otherwise lethal dose of this compound administered 5 to 7 days later. The time course of this effect closely paralleled the higher glutathione and glutathione transferase levels, suggesting a correlation between these effects.
Animals↗
Dispensing and weighing apparatus for alginate impression material.
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Dental Equipment↗