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(1/159) Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity.

The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a murine monoclonal recognizing the surface domain of the TAG-72 antigen and has been widely used in human clinical trials. After our initial encouraging studies (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer, we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p. administration. In the first arm of the study, patients (3 pts/dose level) received an i.p. infusion of either 2 or 10 mg of B72.3 labeled with either 1, 10, 15, or 25 mCi of 90Y. Pharmacokinetic studies demonstrated that concentrations of 90Y-labeled B72.3 persist in peritoneal fluid with half-lives >24 h after i.p. administration. In addition, 90Y-labeled B72.3 was absorbed rapidly into the plasma with peak levels achieved within 48 h, and levels declined slowly thereafter. Cumulative urinary excretion of the 90Y label was 10-20% of the administered dose which suggests significant whole-body retention of the radiolabel. Biopsy specimens of bone and marrow obtained at 72 h after administration demonstrated significant content of the label in bone (0.015% of the dose/g) with relatively little in marrow (0.005% of the dose/g). The maximal tolerated dose was determined to be 10 mCi because of hematological toxicity and platelet suppression. This typically occurred on the 29th day after administration and was thought to be a consequence of the irradiation of the marrow from the bony deposition of the radiolabel. In an effort to suppress the bone uptake of 90Y, patients were treated with a continuous i.v. infusion of EDTA (25 mg/kg/12 h x 6) infused immediately before i.p. administration of the radiolabeled antibody. Patients (3 pts/dose level) were treated with doses of 10, 15, 20, 25, 30, 35, 40, or 45 mCi of 90Y-labeled B72.3 for a total of 38 patients. EDTA administration resulted in significant myeloprotection, which allowed escalation to the maximal tolerated dose of 40 mCi. Dose-limiting toxicity was thrombocytopenia and neutropenia. Studies of plasma and peritoneal fluid pharmacokinetics demonstrate no changes compared with patients without EDTA pretreatment. Cumulative urinary excretion of the radiolabel was not increased in patients pretreated with EDTA compared with the untreated group. However, analysis of biopsy specimens of bone and marrow demonstrated that bone and marrow content of the 90Y label was 15-fold lower (<0.001% injected dose/g) than a companion group without EDTA. Four responses were noted in patients who received 15-30 mCi of 90Y-labeled B72.3 with response durations of 1-12 months. These results demonstrate the myeloprotective ability of EDTA, which allows safe i.p. administration of higher doses of 90Y-labeled B72.3 and, therefore, clearly warrant an expanded Phase II trial in patients with minimal residual disease after standard chemotherapy or for the palliation of refractory ascites.  (+info)

(2/159) The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents III: the effect of the ligands on molecular targets involved in proliferation.

We have identified specific iron (Fe) chelators of the pyridoxal isonicotinoyl hydrazone (PIH) class that are far more effective ligands than desferrioxamine (DFO; Richardson et al, Blood 86:4295, 1995; Richardson and Milnes, Blood 89:3025, 1997). In the present study, we have compared the effect of DFO and one of the most active chelators (2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone; 311) on molecular targets involved in proliferation. This was performed to further understand the mechanisms involved in the antitumor activity of Fe chelators. Ligand 311 was far more active than DFO at increasing Fe release from SK-N-MC neuroepithelioma and BE-2 neuroblastoma cells and preventing Fe uptake from transferrin. Like DFO, 311 increased the RNA-binding activity of the iron-regulatory proteins (IRPs). However, despite the far greater Fe chelation efficacy of 311 compared with DFO, a similar increase in IRP-RNA binding activity occurred after 2 to 4 hours of incubation with either chelator, and the binding activity was not inhibited by cycloheximide. These results suggest that, irrespective of the Fe chelation efficacy of a ligand, an increase IRP-RNA binding activity occurred via a time-dependent step that did not require protein synthesis. Further studies examined the effect of 311 and DFO on the expression of p53-transactivated genes that are crucial for cell cycle control and DNA repair, namely WAF1, GADD45, and mdm-2. Incubation of 3 different cell lines with DFO or 311 caused a pronounced concentration- and time-dependent increase in the expression of WAF1 and GADD45 mRNA, but not mdm-2 mRNA. In accordance with the distinct differences in Fe chelation efficacy and antiproliferative activity of DFO and 311, much higher concentrations of DFO (150 micromol/L) than 311 (2.5 to 5 micromol/L) were required to markedly increase GADD45 and WAF1 mRNA levels. The increase in GADD45 and WAF1 mRNA expression was seen only after 20 hours of incubation with the chelators and was reversible after removal of the ligands. In contrast to the chelators, the Fe(III) complexes of DFO and 311 had no effect on increasing GADD45 and WAF1 mRNA levels, suggesting that Fe chelation was required. Finally, the increase in GADD45 and WAF1 mRNAs appeared to occur by a p53-independent pathway in SK-N-MC and K562 cells, because these cell lines lack functional p53. Our results suggest that GADD45 and WAF1 may play important roles in the cell cycle arrest observed after exposure to these chelators.  (+info)

(3/159) The influence of hemochromatosis mutations on iron overload of thalassemia major.

BACKGROUND AND OBJECTIVE: Hemochromatosis is a genetic form of iron overload due to a defective HFE gene. Secondary iron overload is the main complication in transfusion-dependent thalassemia patients. In this work we have examined the prevalence of HFE mutations in thalassemia major and evaluated the degree of iron overload of patients with and without HFE mutations. DESIGN AND METHODS: HFE mutations were studied in 71 Italian thalassemic patients and in 189 normal controls, using PCR and restriction enzyme analysis. The degree of iron overload, assessed by serum ferritin and liver iron concentration (LIC), was compared in 17 patients with mutations in the HFE gene, and in 17 subjects with wild type HFE genotype. The two groups of patients had comparable globin gene mutations, were matched for age and were homogeneous for transfusion and chelation history. In all cases the iron balance calculated on the basis of transfusion regimen and iron excreted by chelation was available. RESULTS: The allele frequencies of C282Y and H63D were respectively 1.4% and 12.7% in patients and 1.1% and 11.4% in controls. No case of C282Y homozygosity was recorded among patients. No significant difference was found in terms of serum ferritin, LIC, or the age at chelation start between patients with and without HFE mutations. The single patient with H63D homozygosity was severely iron-loaded. INTERPRETATION AND CONCLUSIONS: Our data suggest that the presence of a single mutation in the HFE gene does not influence the severity of iron loading in thalassemia patients following a regular transfusion and chelation program.  (+info)

(4/159) Beta-thalassemia and pulmonary function.

BACKGROUND AND OBJECTIVE: The survival of patients with beta-thalassemia major and intermedia has improved considerably. This has focused attention on the long-term sequelae of the disease itself and its treatment. The effect of hemosiderosis in major organs (heart, liver, etc) are well-recognized, but the pathophysiology of any lung damage is less clearly understood. We studied lung function changes in 32 patients with beta-thalassemia. DESIGN AND METHODS: Respiratory function tests, CO diffusion and arterial blood gas analysis were performed on 19 patients with beta-thalassemia major (9 F, 10 M) and 13 with beta-thalassemia intermedia (6 M, 7 F). All investigations were performed 24 hours before the patients received a blood transfusion or when they were in a stable state hematologic condition. Echocardiography was performed in all patients and the ejection fraction was employed as a measure of cardiac function. RESULTS: No patient had clinical signs of pulmonary dysfunction. Pulmonary function tests, however, showed a reduction of all main parameters (TLC, FVC, FEV1 and RV) in most patients with beta-thalassemia major, indicating a restrictive type of dysfunction. The pulmonary function of patients with beta-thalassemia intermedia seemed to be preserved. Arterial blood gas values were within the normal range, while in some subjects CO diffusion approached the lower limits of normality. There was no evidence that the observed abnormalities in pulmonary function were secondary to congestive heart failure. INTERPRETATION AND CONCLUSIONS: Iron deposition due to repeated blood transfusions may play a central role in determining lung alterations although the majority of patients are well chelated, suggesting that more than one causal mechanisms could be involved.  (+info)

(5/159) Second marrow transplants for graft failure in patients with thalassemia.

Thirty-two thalassemic patients with a median age of 7.7 years (range 3.4-26 years) were given a second HLA-identical related marrow transplant (BMT2) for graft failure. Four patients were in class 1 and 28 patients in classes 2 and 3. Twenty-one patients had full thalassemia recurrence (first group) and 11 patients had aplastic marrows (second group) either with or without residual donor marrow cells after the first BMT (BMT1). As conditioning regimen for BMT2 all but five patients received BUCY or CY in association with total lymphoid irradiation (TLI) and/or anti-lymphocyte globulin (ALG), whereas nine patients received a new preparative regimen with hydroxyurea, azathioprine, fludarabine before conditioning with BUCY. Twenty one of 31 evaluable patients (67.7%) had initial, and 16 (51.6%) had sustained engraftment. Ten patients (32.3%) failed to engraft. Overall and event-free survival for the entire group of patients were 49% and 33%, respectively, with a median follow-up of 4 years (range 0.6-14 years) for surviving patients. Event-free survival was higher in the second group of patients compared with the first group (41% vs 29%). The second group of patients appeared to have less graft failure compared with the first group (30% vs 63%; P = 0.1). Transplant-related mortality was 28%. A linear stepwise regression analysis revealed that occurrence of graft failure within 60 days after BMT1 (P = 0.04) and absence of residual donor marrow cells (P = 0.009) predicted for graft failure following BMT2, whereas the occurrence of graft failure after 60 days (P = 0.03) had a positive influence on survival following BMT2. The incidence of grade >/=2 acute GVHD was low (14%). Eight of nine patients who received the new preparative regimen are alive, four without thalassemia. This study shows that BMT2 can be an effective therapy for a proportion of patients with poor survival expectancies despite conventional treatment.  (+info)

(6/159) Juvenile hemochromatosis associated with B-thalassemia treated by phlebotomy and recombinant human erythropoietin.

Juvenile hemochromatosis is a rare genetic disorder that causes iron overload. Clinical complications, which include liver cirrhosis, heart failure, hypogonadotropic hypogonadism and diabetes, appear earlier and are more severe than in HFE-related hemochromatosis. This disorder, therefore, requires an aggressive therapeutic approach to achieve iron depletion. We report here the case of a young Italian female with juvenile hemochromatosis who was unable to tolerate frequent phlebotomy because of coexistent ss-thalassemia trait. The patient was successfully iron-depleted by combining phlebotomy with recombinant human erythropoietin.  (+info)

(7/159) Lightening the lead load in children.

More than 4 percent of preschool-aged children in the United States have blood lead levels above 10 microg per dL (0.50 pmol per L), and these levels have been associated with a decline in IQ. The Centers for Disease Control and Prevention advocates the use of a screening questionnaire to identify lead exposure or toxicity in all children. Primary prevention through the removal of lead from gasoline and paint has led to a reduction of blood lead levels in children. Secondary prevention through paint hazard remediation is effective in homes that have a high lead burden. Children with lead levels of 45 to 69 microg per dL (2.15 to 3.35 pmol per L) should receive chelation therapy using succimer (DMSA) or edetate calcium disodium (CaNa2EDTA). Use of both CaNa2EDTA and dimercaprol (BAL in oil) is indicated in children with blood lead levels higher than 70 microg per dL (3.40 micromol per L). Current treatment recommendations are based on the reduction of blood lead levels, which may not represent a significant overall reduction of the lead burden. Clinical trials of existing agents are needed to determine patient-oriented outcomes, such as the effect on IQ.  (+info)

(8/159) Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron, used for assessing chelation therapy.

This study introduces a method for monitoring a component of serum non-transferrin-bound iron (NTBI), termed "desferrioxamine-chelatable iron" (DCI). It is measured with the probe fluorescein-desferrioxamine (Fl-DFO), whose fluorescence is stoichiometrically quenched by iron. DCI was found in the serum of most patients with thalassemia major (21 of 27 tested, range 1.5-8.6 microM), but only in a minority of patients with hereditary hemochromatosis (8 of 95 samples from 39 patients, range 0.4-1.1 microM) and in none of 48 controls. The method was applied to monitoring the appearance of iron in the serum of patients under chelation therapy. Short-term (2 hours) follow-up of patients immediately after oral administration of deferriprone (L1) showed substantial mobilization of DCI into the serum (up to 10 microM within 30-60 minutes). The transfer of DCI from L1 to Fl-DFO was observed in vitro with preformed L1-iron complexes, and occurred even at L1/iron ratios exceeding 3:1. Simultaneous administration of oral L1 and intravenous DFO to patients abrogated the L1-mediated rise in DCI, consistent with the shuttling of iron from L1 to DFO in vivo. A similar iron transfer from L1 to apo-transferrin was observed in vitro, lending experimental support to the notion that L1 can shuttle iron in vivo to other high-affinity ligands. These results provide a rationale for using chelator combinations, with the highly permeant L1 acting as an intracellular chelator-shuttle and the less permeant DFO serving as an extracellular iron sink. Potential applications of the DCI assay may be for studying chelator action and as an index of patient chelation status.  (+info)