EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104.

BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.

Biweekly fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) for patients with metastatic adenocarcinoma of the stomach or esophagogastric junction: a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie.

BACKGROUND: The combination of docetaxel (Taxotere), cisplatin, and fluorouracil improved efficacy in gastric cancer, but was associated with substantial toxicity. This study was designed to incorporate docetaxel into a tolerable biweekly (once every 2 weeks) oxaliplatin-based chemotherapy regimen. PATIENTS AND METHODS: Patients with measurable, metastatic adenocarcinoma of the stomach or esophagogastric junction and no prior chemotherapy received oxaliplatin 85 mg/m(2), leucovorin 200 mg/m(2), and fluorouracil 2600 mg/m(2) as a 24-h infusion in combination with docetaxel 50 mg/m(2) (FLOT) on day 1 every 2 weeks. Prophylactic growth factors were not administered. RESULTS: Fifty-nine patients were enrolled; 54 received treatment. Patients had a median age of 60 years (range 29-76) and most (93%) of them had metastatic disease. Objective responses were observed in 57.7% of patients with a median time to treatment response of 1.54 months. Median progression-free survival (PFS) and overall survival were 5.2 and 11.1 months, respectively. Twenty-five percent of patients experienced prolonged (>12 months) PFS. Frequent (>10%) grade 3 or 4 toxic effects included neutropenia in 26 (48.1%), leukopenia in 15 (27.8%), diarrhea in 8 (14.8%), and fatigue in 6 (11.1%) patients. Complicated neutropenia was observed in two (3.8%) patients, only. CONCLUSIONS: Biweekly FLOT is active and has a favorable safety profile.

Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy.

PURPOSE: To evaluate the hypocalcemic effect and safety of three different doses of the bisphosphonate ibandronate in tumor-associated hypercalcemia, and to identify factors predicting response. PATIENTS AND METHODS: One hundred seventy-four cancer patients with a serum calcium level greater than 2.7 mmol/L (10.8 mg/dL) were enrolled onto the trial. If hypercalcemia persisted after fluid repletion, patients were randomly assigned to treatment with 0.6 mg, 1.1 mg, and 2.0 mg of ibandronate. Response, defined as restoration of normocalcemia, was evaluated by an intent-to-treat analysis. RESULTS: One hundred seventy-three (99%) patients were assessable for toxicity and 151 (87%) for efficacy. The administration of 0.6 mg (group A), 1.1 mg (group B), or 2.0 mg (group C) of ibandronate led to response rates of 44%, 52%, and 67%, respectively. Significantly more patients in group C responded than in group A (P = .0276). Of the various parameters examined, only the initial serum calcium level (P < .0001; odds ratio, 0.083) and the dose of ibandronate (P = .0162; odds ratio, 2.094) correlated with response. One hundred ninety-five adverse events (AEs) were reported, 99 classified as serious and 96 as nonserious. Three serious and sixteen nonserious AEs were considered related to ibandronate treatment. The three serious AEs were one case with thrombocytopenia, one with nausea, and one with fever. CONCLUSION: Ibandronate therapy led to a dose-dependent reduction in serum calcium levels. The response to ibandronate treatment correlated negatively with the initial serum calcium level and positively with the dose administered. A dose of 2 mg was necessary to achieve a response rate comparable to that in previous studies with the bisphosphonates pamidronate and clodronate. Because the incidence of drug-associated AEs was low, a dose escalation of ibandronate can be recommended for further clinical trials.

Oral idarubicin, dexamethasone and vincristine (VID) in the treatment of multiple myeloma.

In order to replace the central venous line necessary for continuous infusion of vincristine and doxorubicin with high-dose dexamethasone (VAD) and to avoid hospitalization, we evaluated the efficacy and toxicity of oral idarubicin, vincristine and dexamethasone (VID) in patients with multiple myeloma. Vincristine (1.6 mg/m2, max 2 mg) was given as a bolus injection on day 1. Idarubicin was given in capsules 10 mg/m2/day for days 1-4 with an intraindividual dose escalation, 40 mg dexamethasone were given on days 1-4, 9-12, 17-20. Treatment cycles were repeated every 28 days. At this interim analysis, 53 patients have been entered into the ongoing trial; 46 patients are evaluable for toxicity. The median age was 60 years (interquartile range, 52-65). 46% were primary or secondary refractory, 20% had previously been treated with VAD and 30% had previously untreated disease, 4% had two or more relapses. Four patients died within 2 months from entry and were considered as early deaths (8.7%). 45% of the 42 patients evaluable for efficacy achieved a partial remission and 26% a minor remission. The median reduction of the M-component was 43% (interquartile range, 25-64%). VID is an effective and convenient alternative to VAD even in relapsed or refractory patients.

Serum parathyroid hormone-related protein levels and response to bisphosphonate treatment in hypercalcemia of malignancy.

The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 +/- 0.7 yr (mean +/- SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 +/- 0.02 mmol/L, mean TRCaI was increased at 3.09 +/- 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40-2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 +/- 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 +/- 0.03 mmol/L (20.0 +/- 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 +/- 0.04 mmol/L GFR (47.6 +/- 8.6%; P < 0.001) and 14.4 +/- 1.7 nmol/mmol (27.6 +/- 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 +/- 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D3, and PTH were +0.7 +/- 0.4 (P = NS), +27.6 +/- 3.0 (P < 0.001), and +2.9 +/- 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.

Plasma vitamin E and beta-carotene concentrations during radiochemotherapy preceding bone marrow transplantation.

Blood from 19 patients was examined for the essential antioxidants alpha-tocopherol and beta-carotene before, during, and after bone marrow transplantation (BMT). Marrow ablation and immunosuppression for BMT conditioning was achieved by treatment with high-dose chemotherapy, mostly combined with total body irradiation. All patients required total parenteral nutrition beginning 1 wk before BMT. After conditioning therapy the concentration of absolute and lipid-standardized alpha-tocopherol and beta-carotene in plasma decreased significantly, presumably as a result of an enhanced breakdown of these antioxidants. The loss of these lipid-soluble antioxidants has to be considered as a possible cause for early posttransplant organ toxicity.

Paclitaxel and weekly 24-hour infusion of 5-fluorouracil/folinic acid in advanced gastric cancer.

The current phase II study evaluates the safety and efficacy of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) and 5-fluorouracil (5-FU) plus folinic acid in patients with advanced gastric cancer. Paclitaxel 175 mg/m2 was given intravenously over 3 hours on days 1 and 22; folinic acid 500 mg/m2 given intravenously over 2 hours followed by 5-FU 2,000 mg/m2 given intravenously over 24 hours was administered on days 1, 8, 15, 22, 29, and 36. Six weeks of treatment were considered one cycle, and each cycle was followed by 2 weeks off treatment. Twenty-two patients (six women and 16 men) with advanced/metastatic gastric cancer were entered on trial. All patients are evaluable for response and toxicity. None had received prior chemotherapy. Radiologically metastatic sites included gastric lymph nodes (64%), liver (36%), lungs (18%), peritoneum (18%), bone (9%), and skin (5%). No complete responses were observed. Seven patients (32%; 95% confidence interval, 12% to 52%) had a partial response. Sites of partial responses included the lungs, skin, lymph nodes, and locally advanced tumor. Twelve patients (55%) had stable disease and three (14%) had disease progression. At a median follow-up of 12 months (range, 1 to 17+ months), the median overall survival for all patients was 11 months (range, 1 to 17+ months; 95% confidence interval, 6.8 to 18.2) and the median progression-free interval was 8 months (range, 1 to 13+ months; 95% confidence interval, 4.7 to 9.8). Severe nonhematologic toxicities were alopecia (45%), fever/infection (9%), diarrhea (5%), and nausea/vomiting (5%). Grade 3/4 neutropenia occurred in three patients (14%). In summary, paclitaxel given every 3 weeks in combination with once-weekly, 24-hour continuous infusions of 5-FU/folinic acid is active in advanced gastric cancer and appears to achieve response rates comparable to regimens like etoposide/folinic acid/5-FU or 5-FU/doxorubicin/methotrexate. The toxicity of this new combination is moderate and allows treatment in an outpatient setting. Ongoing studies are evaluating the activity of paclitaxel combined with weekly continuous infusions of 5-FU/folinic acid with or without cisplatin.

Phenylhydrazine-induced lipid peroxidation of red blood cells in vitro and in vivo: monitoring by the production of volatile hydrocarbons.

Human red blood cells and male Sprague-Dawley rats were treated in vitro and in vivo, respectively, with phenylhydrazine in order to determine whether the release of volatile hydrocarbons can serve as a suitable index for phenylhydrazine-induced red blood cell peroxidation. Lipid peroxidation following phenylhydrazine administration (in vitro experiments: dosage calculated at 0.5-50 mM; in vivo experiments: intraperitoneal injection of 2.8 mg/100 g body wt) was monitored by the release of ethane and pentane measured by gas chromatography. Further hydrocarbons such as ethylene, propane, n-butane, iso-butane and iso-butene were monitored to form a basis of comparison. In vitro haemolysis was also determined during the course of incubation. Red blood cell suspensions yielded more than 15-fold concentrations of propane and more than 2-fold concentrations of iso-butane compared to pentane and ethane yields. Haemoglobin solutions also produced propane and iso-butane in the presence of phenylhydrazine, whereas pentane and ethane were not detectable. Time-course studies revealed that ethane and pentane reached maximum in vitro levels after red blood cell suspensions had been incubated for 2 hr whereas the maximum degree of haemolysis (approximately 60%) was attained between 60 and 90 min following the beginning of phenylhydrazine treatment. The dosage did not affect the final degree of haemolysis. Rats treated with phenylhydrazine exhaled greater concentrations of ethane (6-fold increase) and pentane (2-fold increase) compared to control animals. Exhaled propane showed a 30-fold increase in concentration following drug treatment. Our results suggest that the release of pentane and ethane may be useful in assessing red blood cell lipid peroxidation in the presence of phenylhydrazine in vitro and in vivo.

Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists.

The effects of daily dietary supplementation for 6 weeks with either 4.5 g eicosapentaenoic acid (EPA) and 3.35 g docosahexaenoic acid (DHA) (group I, EPA/DHA = 1.33) or 3.5 g EPA and 6.4 g DHA (group II, EPA/DHA = 0.54) on platelet responsiveness to the stable prostaglandin (PG)-endoperoxide analogue 9,11-dideoxy,9 alpha-11 alpha-methanoepoxy-PGF2 alpha (U 46619) were studied in healthy volunteers. Dose-response curves (DRC) of U 46619-induced platelet aggregation were analysed by computerized non-linear curve fitting. In group I, the concentration of U 46619 required for half-maximum platelet aggregation (EC50) remained unchanged, whereas the Hill coefficient decreased from 6.2 to 3.3 (P < 0.02). In group II, characterized by a high intake of DHA, a considerable increase of EC50 from 0.3 to 1.4 microM was found (P < 0.02). These results suggest different effects of EPA and DHA on the platelet thromboxane/endoperoxide-amplifying system. The considerable shift of the DRC in group II suggests a direct effect of DHA on the presentation of the endoperoxide receptor and/or post-receptoral events.

Hereditary lecithin-cholesterol acyltransferase deficiency. Case report of a German patient.

Lecithin-cholesterol acyltransferase (LCAT) deficiency was first described in a Norwegian family as an inborn error of metabolism. Altogether, 35 patients in 18 families have been identified. The authors report the first German patient, who presented with the characteristic clinical features of corneal opacity, proteinuria, and mild anemia. Renal biopsy revealed foam cells and an increased mesangial matrix in the glomeruli. Confirmation of the clinical diagnosis of LCAT deficiency was obtained by plasma enzyme and lipid analyses. Functional LCAT activity was not detected in incubated plasma by chemical or radiochemical methods, although rocket immunoelectrophoresis indicated that the patient had about one-third of normal LCAT mass. In keeping with other reports of LCAT deficiency, apoE-rich discoidal particles were seen in the patient's high-density lipoprotein fraction by electron microscopic examination.

QBEND10 for the diagnosis of myelodysplastic syndromes in routinely processed bone marrow biopsy specimens.

AIM: The assessment of the value of the antibody QBEND10, which is directed against the haemopoietic stem cell related antigen CD34, in the immunohistochemical diagnosis of myelodysplastic syndrome in routinely processed bone marrow biopsy specimens. METHODS: 581 formalin fixed, paraffin embedded trephine biopsy specimens of the iliac crest were immunostained with QBEND10 (avidin-biotin complex/ABC method). The number of CD34+ haemopoietic stem cells/blast cells (referred to hereafter as CD34+ cells) was determined in each case. The Wilcoxon test was used for statistical analysis. RESULTS: The following diagnostic categories were defined: (1) normal or reactive bone marrow (n = 356), (2) lymphoproliferative disorders, usually non-Hodgkin's lymphoma of low grade malignancy or multiple myeloma (n = 118), (3) myelodysplastic syndrome (n = 22), (4) acute leukaemia (n = 44), and (5) myeloproliferative diseases (n = 41). The average number of CD34+ cells was very low (0.2/HPF) in normal and reactive bone marrow, in lymphoproliferative disorders and in the myelodysplastic syndrome subtypes RA and RARS. Myeloproliferative diseases showed an average of three CD34+ cells/HPF. However, the average number of CD34+ cells was significantly higher (p < 0.05) in the myelodysplastic syndrome subtypes RAEB and RAEB-T (8.7/HPF) and in acute leukaemia (including both myeloid and lymphoblastic leukaemia; 111.7/HPF). CONCLUSIONS: QBEND10 is of value for the identification of RAEB and RAEB-T in routinely processed bone marrow biopsy specimens because it enables the detection of even small increases in the number of CD34+ cells.

Effect of etoposide (VP16-213) on lipid peroxidation and antioxidant status in a high-dose radiochemotherapy regimen.

A total of 13 patients receiving bone marrow transplants (BMT) for treatment of different haematological diseases were investigated. Conditioning therapy preceding BMT consisted of fractionated total-body irradiation (12 Gy) and high-dose chemotherapy with cyclophosphamide (2 +/- 60 mg/kg). Patients stratified to be at high risk for relapse (6/13) were additionally treated with etoposide (30 mg/kg). Plasma concentrations of absolute and lipid-standardized antioxidants (alpha-tocopherol and beta-carotene) decreased following conditioning therapy, presumably as the result of an enhanced breakdown of these antioxidants. Etoposide treatment did not amplify the loss of essential anti-oxidants but significantly increased lipid hydroperoxide concentrations in serum. We suggest that the abnormal generation of lipid hydroperoxides is the result of free radical formation.

Decreased susceptibility of red blood cells to lipid peroxidation in patients with alcoholic liver cirrhosis.

Red blood cells from alcoholics with and without liver cirrhosis and control subjects were examined for the susceptibility to lipid peroxidation. Red blood cells of patients with liver cirrhosis were found to be less sensitive to hydrogen peroxide-induced peroxidation measured by a new, reliable and sensitive method: the release of pentane during red blood cell lipid peroxidation. Changes of sensitivity to lipid peroxidation correlated with the severity of the liver malfunction, but not with abnormalities of the lipid composition of red cell membranes which are apparent in patients with liver disease. In alcoholics without liver cirrhosis, only minor changes in the susceptibility of red cells to peroxidation were observed.

Plasma and red cell lipids in alcoholics with macrocytosis.

The cholesterol and phospholipid content and the fatty acid composition in plasma and red cell membranes was determined in 10 alcoholics with macrocytic erythrocytes. None of the patients had anemia. Red cells exhibited macrocytosis up to 108 fl in all patients. Bilirubin, albumin, prothrombin, and cholinesterase were in the normal range, whereas transaminases and gamma-glutamyl transpeptidase activities in serum were elevated in most of the patients. The molar ratio cholesterol/phospholipids in red cells was not altered in alcoholics. An abnormally high ratio of saturated/unsaturated fatty acids was found in plasma as well as in red cell phospholipids from alcoholics. Linoleic acid was substantially decreased in plasma of alcoholics (controls 32.3%, alcoholics 21.8%). This fatty acid abnormality was reflected by a decrease of linoleic acid in red cell phosphatidylcholine. The present data may suggest that fatty acid changes taking place in membranes of macrocytes were a consequence of changes in the plasma and reflect plasma/membrane exchanges rather than direct effects of ethanol on red cell membranes. Lipid alterations of red cell membranes may be involved in the development of macrocytosis in chronic alcoholism.

Lipid peroxidation in erythrocytes.

Erythrocytes might be expected to be highly susceptible to peroxidation. Their membranes are rich in polyunsaturated fatty acids; they are continuously exposed to high concentrations of oxygen; and they contain a powerful transition metal catalyst. In fact, autoxidation is held in check in vivo by extremely efficient protective antioxidant mechanisms. These involve cellular enzymes such as superoxide dismutase and glutathione peroxidase, as well as vitamin E; but they mainly reflect effective structural compartmentalisation. This review surveys mechanisms which lead to red cell lipid autoxidation and the role of haemoglobin in these processes. The influence of haemoglobinopathies, of lipid composition and of abnormalities in antioxidant mechanisms induced by exogenous oxidant stress is also considered.

Effect of dietary phytochemicals on cancer development (review)

Vegetables, fruits, and whole grains contain a wide variety of phytochemicals that have the potential to modulate cancer development. There are many biologically plausible reasons why consumption of plant foods might slow or prevent the appearance of cancer. These include the presence in plant foods of such potentially anticarcinogenic substances as carotenoids, chlorophyll, flavonoids, indole, isothiocyanate, polyphenolic compounds, protease inhibitors, sulfides, and terpens. The specific mechanisms of action of most phytochemicals in cancer prevention are not yet clear but appear to be varied. Considering the large number and variety of dietary phytochemicals, their interactive effects on cancer risk may be extremely difficult to assess. Phytochemicals can inhibit carcinogenesis by inhibiting phase I enzymes, and induction of phase II enzymes, scavenge DNA reactive agents, suppress the abnormal proliferation of early, preneoplastic lesions, and inhibit certain properties of the cancer cell.

Supplementation with antioxidants prior to bone marrow transplantation.

Conditioning therapy preceding bone marrow transplantation (BMT) usually consists of high-dose chemotherapy and total body irradiation (TBI). It has acute and delayed toxic effects on several tissues, possibly related to peroxidation processes and exhaustion of antioxidants. Early studies indicated an increase of peroxide processes and a decrease of antioxidants during conditioning therapy. Hence, we investigated the effect of antioxidant supplementation on peroxidation processes and antioxidant status. We supplemented a patient group (N = 16) [BMT (+)], with oral 45 mg beta-carotene, 825 mg alpha-tocopherol and 450 mg ascorbic acid daily for three weeks before conditioning therapy. Another patient group (N = 10), BMT(-), was not supplemented with antioxidants before conditioning therapy. In order to investigate the physiologic effect of supplement antioxidants a healthy control group (N = 10) was supplemented with the same doses as BMT(+). Peroxide concentrations in plasma were measured by using the cholesterol oxidase (CHOD)-iodide method and antioxidants were measured by HPLC. Before supplementation the beta-carotene and alpha-tocopherol concentrations were comparable in both patient groups. After supplementation significantly higher beta-carotene and alpha-tocopherol concentrations were measured in the supplemented patients, BMT(+), than in the unsupplemented patients, BMT(-). After conditioning therapy, BMT(+) patients showed a significantly higher beta-carotene concentration (p < 0.05) than before supplementation. In BMT(-) patients the beta-carotene (p < 0.05) and alpha-tocopherol concentrations (p < 0.01) decreased significantly and the lipid peroxide concentration increased significantly following conditioning therapy. We conclude that antioxidant supplementation prior to conditioning therapy reduces peroxidation processes induced by conditioning therapy in bone marrow recipients.

[Vitamins and therapy of malignancies]. / Vitamine und Therapie von Malignomen.

Conditioning therapy preceding bone marrow transplantation usually consists of high-dose chemotherapy and total body irradiation. This is associated with acute and delayed toxic effects for several tissues, possibly related to peroxidation processes and exhaustion of antioxidants. Therefore, plasma of 22 patients was examined for alpha- and gamma-tocopherol (vitamin E), the carotenoids beta-carotene and lycopene, retinol, and ascorbic acid before, during and after conditioning chemotherapy for bone marrow transplantation. 18 of the patients received total body irradiation as well. Retinol and ascorbic acid have been given intravenously in a multiple of the recommended doses (Deutsche Gesellschaft für Ernährung (DGE) and Recommended Dietary Allowance (RDA), respectively). The doses chosen were sufficient to maintain the initial plasma concentrations of these vitamins. However, alpha-tocopherol (in RDA doses) and beta-carotene (no RDA established) concentrations deteriorated after the conditioning therapy (20% and 50% loss, respectively). The loss of these lipid-soluble antioxidants has been considered to result from lipid peroxidation, since lipid peroxide concentrations in plasma increased concurrently. On the basis of these results we performed interventions studies in order to investigate the effect of high-dose supplementation on antioxidant status. We compared the loss of antioxidants and the toxicity in two groups of patients undergoing bone marrow transplantation: The first group without and the second group with oral supplementation of high doses of alpha-tocopherol (825 mg daily), ascorbic acid (450 mg daily) and beta-carotene (45 mg daily) for three weeks prior to chemo- and radiotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)