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Biomedical subjects

D E Myers

Publications and source records attributed to D E Myers.

At least 19 recordsLinked to original sources
PubMed2004

Expression of the skate (Raja erinacea) AE1 osmolyte channel in Xenopus laevis oocytes: monovalent cation permeability.

The aim of this study was to express the cloned skate anion exchanger 1 (skAE1) in Xenopus oocytes and determine whether the differences in monovalent cation permeabilities in hypotonically stimulated skate and trout erythrocytes could be due to differences in the presence or absence of intracellular channel regulators between the two species or in the intrinsic permeability properties of the channels themselves. The expressed protein (skAE1) was inserted into the oocyte cell membrane and facilitated both Cl- exchange and taurine transport. Expression of skAE1 in oocytes showed similar monovalent cation permeabilities as previously reported for skate erythrocytes and different from both trout erythrocytes and trAE1 expressed in Xenopus oocytes. These results show that the skAE1 expressed in oocytes functions in a manner similar to that of the osmolyte channel in hypotonically activated skate erythrocytes and supports the hypothesis that differences in the monovalent cation permeabilities of the osmolyte channels in skate and trout RBCs resides in the differences in permeability properties of the channels between the two species.

Animals↗
PubMed2002

Leptin directly regulates bone cell function in vitro and reduces bone fragility in vivo.

Fat mass is an important determinant of bone density, but the mechanism of this relationship is uncertain. Leptin, as a circulating peptide of adipocyte origin, is a potential contributor to this relationship. Recently it was shown that intracerebroventricular administration of leptin is associated with bone loss, suggesting that obesity should be associated with low bone mass, the opposite of what is actually found. Since leptin originates in the periphery, an examination of its direct effects on bone is necessary to address this major discrepancy. Leptin (>10(-11) m) increased proliferation of isolated fetal rat osteoblasts comparably with IGF-I, and these cells expressed the signalling form of the leptin receptor. In mouse bone marrow cultures, leptin (>or=10(-11) m) inhibited osteoclastogenesis, but it had no effect on bone resorption in two assays of mature osteoclasts. Systemic administration of leptin to adult male mice (20 injections of 43 micro g/day over 4 weeks) reduced bone fragility (increased work to fracture by 27% and displacement to fracture by 21%, P<0.001). Changes in tibial histomorphometry were not statistically significant apart from an increase in growth plate thickness in animals receiving leptin. Leptin stimulated proliferation of isolated chondrocytes, and these cells also expressed the signalling form of the leptin receptor. It is concluded that the direct bone effects of leptin tend to reduce bone fragility and could contribute to the high bone mass and low fracture rates of obesity. When administered systemically, the direct actions of leptin outweigh its centrally mediated effects on bone, the latter possibly being mediated by leptin's regulation of insulin sensitivity.

Animals↗
PubMed2001

Type 1 diabetes mellitus and oral health: assessment of coronal and root caries.

OBJECTIVES: The oral health of a large cohort of adult insulin-dependent diabetic patients (Type 1), diagnosed 24 years previously with juvenile onset, was comprehensively assessed. This paper describes the prevalence of coronal and root caries in this adult Type 1 diabetic population and evaluates demographic, dietary, behavioral, physiologic, salivary and medical variables associated with decayed and filled surfaces in the crown (DFS) or root (RDFS). METHODS: Type 1 diabetes mellitus subjects participating in this oral health evaluation had been monitored for 6-8 years as participants in the University of Pittsburgh, Department of Epidemiology, longitudinal study of medical complications associated with diabetes. Four hundred and six diabetic subjects received a comprehensive oral health examination during one of their regularly scheduled medical visits. Oral assessments included coronal and root caries, missing teeth, edentulism, periodontal status, soft tissue pathologies, salivary function and health behaviors. Sixteen diabetic subjects and one control subject were edentulous. Coronal and root caries data from the remaining 390 dentate diabetic subjects were compared with 202 dentate nondiabetic control subjects. RESULTS: The adult Type 1 diabetic subjects were not found to have significantly higher DFS rates as compared with our control subjects or published age-adjusted NHANES III findings. Both control and diabetic subjects had low decayed to filled tooth surface ratios. A linear regression model evaluated possible associations with coronal decayed and filled tooth surfaces (DFS) within the diabetic population. Significant factors included older age, women, fewer missing teeth, more frequent use of dental floss, more frequent visits to the dentist during the last 12 months, and diabetic nephropathy. The prevalence of RDFS was higher in the diabetic subjects as compared to recruited control subjects. Neither dietary behaviors nor glycemic control were found to contribute to coronal or root caries. CONCLUSIONS: Factors associated with presence of coronal and root caries and fillings are discussed. Possible causes and implications for the association between DFS and diabetic nephropathy are provided.

Adult↗
PubMed2000

EGF-genistein inhibits neointimal hyperplasia after vascular injury in an experimental restenosis model.

A murine model of vascular injury-induced neointimal hyperplasia was developed by using a photoactive dye, rose bengal. Photoactivation of rose bengal induced vascular injury to the femoral arteries of C57B1/6 mice and resulted in an occlusive neointimal hyperplasia after 4 weeks. The cellular elements of the hyperplastic neointima were found to be alpha-actin-positive vascular smooth muscle cells expressing epidermal growth factor (EGF) receptor at high levels. EGF-Gen, an EGF-R-specific inhibitor with potent anticancer activity, suppressed the formation of hyperplastic neointima. Morphometric analysis of serial tissue sections at 4 weeks after vascular injury showed that in 75% of the EGF-Gen-treated mice, the maximal stenosis index was only 0.44 +/- 0.13, whereas in 75% of phosphate-buffered saline (PBS)-treated mice, the maximal stenosis index was 1.20 +/- 0.25. The mean neointima/media ratios for areas of maximum neointimal hyperplasia were 0.59 +/- 0.16 (n = 24) for the EGF-Gen-treated group, 0.99 +/- 16 (n = 45) for the PBS group (EGF-Gen vs. PBS, p = 0.0017), and 1.03 +/- 18 (n = 8) for group treated with unconjugated genistein (EGF-Gen vs. Gen, p = 0.0088). EGF-Gen treatment of mice with vascular injury to the left femoral artery was not associated with any clinical signs of toxicity or histopathologic lesions in any of the organs, including the uninjured right femoral artery. EGF-Gen also inhibited VSMC migration in vitro, without affecting VSMC proliferation and viability, suggesting that EGF-Gen is blocking neointima formation by inhibiting cellular migration to vascular injury sites. In conclusion, EGF-Gen may be useful as a nontoxic prophylactic agent for prevention of restenosis in clinical settings.

Animals↗
PubMed2000

Induction of osteoclasts from CD14-positive human peripheral blood mononuclear cells by receptor activator of nuclear factor kappaB ligand (RANKL).

Osteoclasts are bone-resorbing cells that are derived from haemopoietic precursors, including cells present in peripheral blood. The recent identification of RANKL [receptor activator of nuclear factor (NF)-kappaB ligand], a new member of the tumour necrosis factor ligand superfamily that has a key role in osteoclastogenesis, has allowed the in vitro generation of osteoclasts in the absence of cells of the stromal/osteoblast lineage. Human peripheral blood mononuclear cells (PBMC) cultured in vitro with soluble RANKL and human macrophage colony-stimulating factor form osteoclasts. However, PBMC are heterogeneous, consisting of subsets of monocytes and lymphocytes as well as other blood cells. As the CD14 marker is strongly expressed on monocytes, the putative osteoclast precursor in peripheral blood, we have selected CD14(+) cells from PBMC to examine their osteoclastogenic potential and their expression of novel members of the tumour necrosis factor superfamily involved in osteoclastogenesis. Highly purified CD14(+) cells demonstrated mRNA expression of receptor activator of NF-kappaB, but no expression of RANKL or osteoprotegerin, whereas PBMC expressed mRNAs for all three factors. CD14(+) (but not CD14(-)) cells cultured on bone slices for 21 days with human macrophage colony-stimulating factor and soluble RANKL generated osteoclasts and showed extensive bone resorption. Similar numbers of osteoclasts were generated by 10(5) CD14(+) cells and 10(6) PBMC, but there was significantly less intra-assay variability with CD14(+) cells, suggesting the absence of stimulatory/inhibitory factors from these cultures. The ability of highly purified CD14(+) cells to generate osteoclasts will facilitate further characterization of the phenotype of circulating osteoclast precursors and cell interactions in osteoclastogenesis.

Bone Resorption↗
PubMed1999

Expression of functional RANK on mature rat and human osteoclasts.

Although the important roles of RANK/RANKL in osteoclastogenesis have been established, their roles in the regulation of mature osteoclasts remain uncertain. Microisolation has been used to obtain pure populations of rat and human osteoclasts for RT-PCR analysis. RANK and calcitonin receptor mRNA was detected in all the samples whereas OPG and ALP mRNA was not present in any. RANKL mRNA was detected in two of eight rat and one of four human samples. Treatment of osteoclasts with soluble RANKL resulted in translocation of NF-kappaB to the nucleus and elevation of cytosolic and nuclear calcium levels. We have shown that RANK is highly expressed in mature osteoclasts and that its stimulation by RANKL results in activation of NF-kappaB and calcium signalling.

Animals↗
PubMed1999

Potential neurogenic and vascular roles of nitric oxide in migraine headache and aura.

It has long been known that nitrate and nitrite medications consistently cause significant headache as a side effect. Classical research has shown that cerebral vasodilation accompanies the use of these medications. More modern studies suggest that these vasodilators exert their action on blood vessels via nitric oxide and its second messenger, cyclic guanosine monophosphate. This paper reviews research studies and theoretical articles which address the concept that nitric oxide plays a major role in the vasodilation associated with the headache phase of migraine with aura. A brief discussion of nitric oxide biochemistry and pharmacology follows. In addition, there is a review of evidence examining the possible contributions of nitric oxide to the neurogenic and vascular events associated with spreading cortical depression, an animal model of migraine aura. The paradoxical hypotheses that nitric oxide may contribute to both the propagation of spreading cortical depression and its limitation are presented. Finally, a rationale for the experimental use of nitric oxide agonists and antagonists in the abortion of migraine aura is introduced.

Animals↗
PubMed1999

X-ray crystallographic analysis of the structural basis for the interactions of pokeweed antiviral protein with its active site inhibitor and ribosomal RNA substrate analogs.

The pokeweed antiviral protein (PAP) belongs to a family of ribosome-inactivating proteins (RIP), which depurinate ribosomal RNA through their site-specific N-glycosidase activity. We report low temperature, three-dimensional structures of PAP co-crystallized with adenyl-guanosine (ApG) and adenyl-cytosine-cytosine (ApCpC). Crystal structures of 2.0-2.1 A resolution revealed that both ApG or ApCpC nucleotides are cleaved by PAP, leaving only the adenine base clearly visible in the active site pocket of PAP. ApCpC does not resemble any known natural substrate for any ribosome-inactivating proteins and its cleavage by PAP provides unprecedented evidence for a broad spectrum N-glycosidase activity of PAP toward adenine-containing single stranded RNA. We also report the analysis of a 2.1 A crystal structure of PAP complexed with the RIP inhibitor pteoric acid. The pterin ring is strongly bound in the active site, forming four hydrogen bonds with active site residues and one hydrogen bond with the coordinated water molecule. The second 180 degrees rotation conformation of pterin ring can form only three hydrogen bonds in the active site and is less energetically favorable. The benzoate moiety is parallel to the protein surface of PAP and forms only one hydrogen bond with the guanido group of Arg135.

Binding Sites↗
PubMed1999

Clinical pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in patients with B-lineage lymphoid malignancies.

The authors examined the pharmacokinetics of the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein in 17 patients (4 children, 13 adults) with B-lineage lymphoid malignancies, including 12 patients with acute lymphoblastic leukemia (ALL) and 5 patients with non-Hodgkin's lymphoma (NHL). The immunoconjugate was administered intravenously as a 1-hour continuous infusion at a dose level of either 0.1 mg/kg (N = 12) or 0.18 mg/kg (N = 5), and the plasma concentration-time data were modeled by using the WinNonlin program to estimate the pharmacokinetic parameters. Pharmacokinetic analyses revealed a plasma half-life of 19 +/- 4 hours, mean residence time of 22 +/- 4 hours, and a systemic clearance of 18 +/- 2 mL/h/kg. The average (mean +/- SEM) values for the maximum plasma concentration Cmax, volume of distribution at steady state (Vss), and area under curve (AUC) were 1092 +/- 225 ng/ml, 291 +/- 37 mL/kg, and 9987 +/- 2021 micrograms x h/L, respectively. The AUC values were higher at the 0.18 mg/kg dose level than at the 0.1 mg/kg dose level (16,848 +/- 5118 micrograms x h/L vs. 7128 +/- 1156 micrograms x h/L, p = 0.009). Patients with ALL had a significantly larger volume of distribution at steady state (332 +/- 47 mL/kg vs. 191 +/- 12 mL/kg, p = 0.04), faster clearance (21 +/- 3 mL/h/kg vs. 11 +/- 2 mL/h/kg, p = 0.03), and lower dose-corrected AUC than patients with NHL (6010 +/- 836 micrograms x h/L vs. 12,044 +/- 2707 micrograms x h/L, p = 0.006). There was a trend toward faster clearance rates (23 +/- 4 mL/h/kg vs. 16 +/- 3 mL/h/kg, p = 0.1), shorter elimination half-lives (5.7 +/- 3.6 hours vs. 13 +/- 8.8 hours, p = 0.1), and shorter mean residence times (11 +/- 3 hours vs. 25 +/- 5 hours, p = 0.08) for non-Caucasian patients as compared to Caucasian patients. When compared to adult patients, pediatric patients showed a significantly larger volume of distribution at steady state (418 +/- 82 mL/kg vs. 252 +/- 34 mL/kg, p = 0.02) and a longer elimination half-lives (18.4 +/- 13.6 hours vs. 8.7 +/- 6.7 hours, p = 0.04). The pharmacokinetics of B43-Genistein was not affected by the gender of the patients or by bone marrow transplantation in past medical history. Overall, B43-Genistein showed favorable pharmacokinetics in this heavily pretreated leukemia/lymphoma patient population, which is reminiscent of its recently reported favorable pharmacokinetics in cynomolgus monkeys. To our knowledge, this is the first clinical pharmacokinetics study of a tyrosine kinase inhibitor containing immunoconjugate.

Adolescent↗
PubMed1999

Type 1 diabetes mellitus and oral health: assessment of periodontal disease.

BACKGROUND: The periodontal disease status of 320 dentate adults, diagnosed 23.7 years previously with Type 1 insulin dependent diabetes mellitus, was evaluated. These patients had been monitored at 2-year intervals as part of a large University of Pittsburgh longitudinal study assessing the medical complications associated with insulin dependent diabetes. METHODS: During one of their regularly scheduled medical examinations, a group of 320 adult dentate subjects (mean age of 32.1 years) received a periodontal examination as part of a comprehensive oral health assessment. The oral health assessment collected data regarding demographics, oral health behaviors, tooth loss, coronal and root caries, salivary functions, and soft tissue pathologies. For the periodontal assessments, 3 facial sites (mesial, midcervical, distal) of the teeth in the right maxillary/left mandibular or left maxillary/right mandibular quadrants were evaluated for calculus, bleeding on probing (BOP) and loss of gingival attachment (LOA). RESULTS: Attachment loss was significantly greater for older patients whereas BOP and calculus levels were relatively constant across age categories. Univariate analyses of factors possibly related to extensive periodontal disease (LOA > or =4 mm for at least 10% of sites examined) indicated an association with older age; lower income and education; past and current cigarette smoking; infrequent visits to the dentist; tooth brushing less than once per day; older age of onset; longer duration of diabetes; and the diabetic complication of neuropathy. A multivariate regression model of all possibly significant factors found current cigarette use (odds ratio [OR] = 9.73), insulin dependent diabetes onset after 8.4 years of age (OR = 3.36), and age greater than 32 years (OR = 3.00) explained the majority of the extensive periodontal disease in this group of diabetic patients. CONCLUSIONS: Management and prevention of extensive periodontal disease for Type 1 diabetic patients should include strong recommendations to discontinue cigarette smoking.

Adult↗
PubMed1999

Treatment of therapy-refractory B-lineage acute lymphoblastic leukemia with an apoptosis-inducing CD19-directed tyrosine kinase inhibitor.

Seven children and eight adults with CD19+ B-lineage acute lymphoblastic leukemia, as well as one adult with chronic lymphocytic leukemia, were treated with the CD19 receptor-directed tyrosine kinase inhibitor B43-Genistein. All patients had failed previous chemotherapy regimens, and six patients had relapsed after bone marrow transplantation. B43-Genistein was administered as a 1-hour i.v. infusion at 0.1-0.32 mg/kg/day dose levels for 10 consecutive days or 3 consecutive days weekly for a total of nine doses. B43-Genistein was well tolerated by all patients with no life-threatening side effects. There were six episodes of grade 2-3 fever, two of which were clearly drug related, one episode each of grade 3 myalgia, grade 2 sinus tachycardia, and grade 2 vascular leak syndrome. There was one durable complete remission and two transient responses. Pharmacokinetic analyses in 12 patients revealed a plasma half-life of 20 +/- 5 h, mean residence time of 24 +/- 5 h, and a systemic clearance rate of 20 +/- 3 ml/h/kg. Moderate levels of human antimouse antibody (HAMA) ranging from 20-87 ng/ml were detected in the day 28 blood samples from three of nine cases examined. Treatment of these three HAMA-positive patients with a second course of B43-Genistein did not yield measurable immunoconjugate levels in the plasma, indicating that the administered B43-Genistein molecules were rapidly cleared from circulation due to the HAMA. On the basis of its acceptable toxicity profile and its ability to elicit objective responses at nontoxic dose levels, B43-Genistein may provide the basis for an effective treatment strategy for B-lineage acute lymphoblastic leukemia patients who have failed standard therapy.

Adolescent↗
PubMed1998

Type 1 diabetes mellitus and oral health: assessment of tooth loss and edentulism.

OBJECTIVE: The oral health of an adult population previously diagnosed with juvenile onset insulin dependent-diabetes was comprehensively assessed. The goal of this exploratory cross-sectional evaluation was to described the characteristics related to partial tooth loss edentulism in subjects with Type 1 diabetes mellitus. METHODS: An adult population of 406 Type 1 diabetes mellitus subjects, who had been monitored for 6-8 years as part of a University of Pittsburgh longitudinal study of medical complications associated with diabetes, received an oral health examination for missing teeth, edentulism, coronal and root caries, periodontal status, and oral health behaviors. RESULTS: Of the 406 subjects evaluated, 204 had no missing teeth, 186 had partial tooth loss (1-27 missing teeth), and 16 were edentulous. Patients who had partial tooth loss or who were edentulous were generally older; had lower incomes and levels of education; and had higher rates of nephropathy, neuropathy, retinopathy, and peripheral vascular disease. A logistic regression model found partial tooth loss to be significantly associated with extensive periodontal disease in remaining teeth (OR = 7.35), a duration of diabetes longer than 24 years (OR = 5.32), not using dental floss (OR = 2.37), diabetic neuropathy (OR = 2.29), household income less than $20,000 (OR = 2.21), multiple coronal caries and fillings (OR = 1.98), and bleeding on probing (OR = 1.82). CONCLUSIONS: Although the majority of these adult Type 1 diabetes patients had serious medical complications associated with their diabetes, the possible impact of diabetes mellitus on oral health should be included in their overall management.

Adolescent↗
PubMed1998

TXU (anti-CD7)-pokeweed antiviral protein as a potent inhibitor of human immunodeficiency virus.

We have evaluated the clinical potential of TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunoconjugate (TXU-PAP) as a new biotherapeutic anti-human immunodeficiency virus (anti-HIV) agent by evaluating its anti-HIV type 1 (anti-HIV-1) activity in vitro, as well as in a surrogate human peripheral blood lymphocyte-severe combined immunodeficient (Hu-PBL-SCID) mouse model of human AIDS. The present report documents in a side-by-side comparison the superior in vitro anti-HIV-1 activity of TXU-PAP compared to the activities of zidovudine, 2',3'-didehydro-2',3'-dideoxythymidine, unconjugated PAP, and B53-PAP, an anti-CD4-PAP immunoconjugate. Notably, TXU-PAP elicited potent anti-HIV activity in the Hu-PBL-SCID mouse model of human AIDS without any side effects and at doses that were very well tolerated by cynomolgus monkeys. Furthermore, plasma samples from TXU-PAP-treated cynomolgus monkeys showed potent anti-HIV-1 activity in vitro.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Reliability of self-reported heart murmur history: possible impact on antibiotic use in dentistry.

Administration of prophylactic antibiotics to a dental patient with a history of heart murmur, rheumatic fever or mitral valve prolapse should be based on a reliable diagnosis of heart valve disease. The authors conducted a study of 68 diabetic patients who reported having these conditions and found that at least 65 percent of these patients actually had no evidence of a pathological heart murmur during two previous physical examinations. They concluded that a self-reported history of heart valve disease should not be the sole criterion for antibiotic premedication.

Adolescent↗
PubMed1998

In vivo toxicity and pharmacokinetic features of B43(Anti-CD19)-Genistein immunoconjugate.

B43(anti-CD19)-Genistein immunoconjugate targets genistein, a naturally occurring protein tyrosine kinase inhibitory isoflavone to the membrane-associated anti-apoptotic CD19-LYN complexes and triggers apoptotic cell death. In this preclinical study, the toxicity profiles of B43-Genistein as well as unconjugated genistein were evaluated in mice. B43-Genistein and genistein were administered either as single bolus injections or daily injections for 10 consecutive days via the intraperitoneal route to mice. Genistein was not toxic to mice at the highest dose of 40 mg/kg and no test article-related histopathological lesions were found in any of the 64 genistein-treated mice. B43-Genistein had a significantly longer elimination half-life and slower plasma and tissue clearance than unconjugated genistein. B43-Genistein was not toxic to mice at the highest single dose of 40 mg/kg or highest cumulative dose of 100 mg/kg and no test article-related histopathological lesions were found in any of the 108 mice treated with B43-genistein. To our knowledge, this is the first preclinical toxicity and pharmacokinetic study of a tyrosine kinase inhibitor-containing immunoconjugate.

Animals↗
PubMed1998

Treatment of human B-cell precursor leukemia in SCID mice by using a combination of the anti-CD19 immunotoxin B43-PAP with the standard chemotherapeutic drugs vincristine, methylprednisolone, and L-asparaginase.

We have compared the antileukemic activity of the investigational biotherapeutic agent B43-PAP to the antileukemic activities of the standard chemotherapeutic drugs vincristine (VCR), methylprednisolone (PDN), L-asparaginase (L-ASP) as single agents as well as in a 3-drug combination regimen ("VPL") using a SCID mouse model of human B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). When mice (N = 95) were challenged with 1 x 10(6) NALM-6 leukemia cells, all of them died of disseminated leukemia with a median event-free survival (EFS) of 47 +/- 6 days. B43-PAP was more active than VCR, PDN, or L-ASP and the two-drug combinations VCR + B43-PAP, PDN + B43-PAP, or L-ASP + B43-PAP were not significantly more active than B43-PAP. The 120 days EFS outcome results were 46 +/- 13% for B43-PAP (Median EFS = 92 +/- 22 days), 0 +/- 0% for VCR (Median EFS = 49 +/- 1 days), 40 +/- 22% for PDN (Median EFS = 100 +/- 20 days), 0 +/- 0% for L-ASP (Median EFS = 41 +/- 1 days), 60 +/- 22% for VCR + B43-PAP (Median EFS = >120 days), 60 +/- 22% for PDN + B43-PAP (Median EFS = >120 days), and 50 +/- 25% for L-ASP + B43-PAP (Median EFS = 93 +/- 27 days), When mice (N = 61) were challenged with 5 x 10(6) NALM-6 cells, all of them rapidly died of disseminated leukemia with a median EFS of 37 +/- 3 days. The 3-drug combination "VPL" (Median EFS = 75 +/- 23 days) was slightly less active than B43-PAP (Median EFS = 84 +/- 19 days) (P = 0.09). Notably, the combination of "VPL" with B43-PAP (i.e., VPLB) resulted in 100% survival. By comparison, the combination of "VPL" with daunorubicin (i.e., VPLD) (Median EFS = 69 +/- 31 days) was not more active than VPL. To our knowledge, this preclinical study is the first to demonstrate the feasibility and superb antileukemic activity of immunochemotherapy using anti-CD19 immunotoxin in combination with the standard 3-drug combination "VPL" against BCP ALL.

Animals↗
PubMed1998

Combined therapeutic efficacy of the thymidylate synthase inhibitor ZD1694 (Tomudex) and the immunotoxin B43(anti-CD19)-PAP in a SCID mouse model of human B-lineage acute lymphoblastic leukemia.

The quinazoline antifolate N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N- methylamino]-2-thenoyl)-L-glutamic acid (ZD1694; Tomudex) is a potent inhibitor of thymidylate synthase and causes cell death through disruption of DNA synthesis and repair by blocking the obligatory thymidine nucleotide synthesis. B43(anti-CD19)-PAP immunotoxin is a potent inhibitor of protein synthesis in CD19+ B-lineage acute lymphoblastic leukemia (ALL) cells and causes apoptosis. In this model, 100% of SCID mice challenged with 1 x 10(6) human NALM-6 B-lineage ALL cells develop overt and invariably fatal leukemia. All of the 22 control SCID mice treated with phosphate-buffered saline died of disseminated human leukemia between 31 and 61 days with a median survival of 41.2 days. Treatment with ZD 1694 resulted in improved leukemia-free survival with a median survival of 69.2 days (P < 0.001, log-rank test). B43-PAP treatment was more effective than ZD1694 (P=0.026) and resulted in 51.0% long-term leukemia-free survival with a median survival of 187.5 days (P < 0.0001. log-rank test). The combination of ZD1694 and B43-PAP was more effective than either agent alone and resulted in 100% long-term leukemia-free survival. To our knowledge, this preclinical study is the first to demonstrate the feasibility and therapeutic advantage of combining an anti-leukemia immunotoxin with a thymidylate synthase inhibitor.

Animals↗