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J A Coderre

Publications and source records attributed to J A Coderre.

88 records · Page 5Linked to original sources
PubMed1987

Selective targeting of boronophenylalanine to melanoma in BALB/c mice for neutron capture therapy.

Melanoma cells actively accumulate aromatic amino acids for use as precursors in the synthesis of the pigment melanin. Using the Harding-Passey melanoma carried s.c. in BALB/c mice, we have demonstrated that p-boronophenylalanine (BPA) is taken up by melanoma tissue to a much greater extent than by normal tissues. Following a single i.p. injection, or a series of injections given over 1 h, the accumulation of boron in melanoma was found to be transient, reaching a maximum approximately 6 h postinjection. The concentrations of boron achieved in tumor ranged from 9-33 micrograms/g, and are within the range estimated to be necessary for successful application of the nuclear reaction 10B(n,alpha)7Li for neutron capture therapy. Boron concentrations in tumor and tissues were determined using either a prompt-gamma spectroscopic technique or by quantitative neutron capture radiography using whole-body sections. Distribution studies with the resolved stereoisomers of BPA indicated that the L isomer is preferentially accumulated in the melanoma compared to the D isomer. The L isomer of BPA was shown to be targeted to actively dividing tumor cells by simultaneously comparing the boron and [3H]thymidine distribution in tumor. Under conditions which selectively deliver high concentrations of boron to Harding-Passey melanomas in BALB/c mice, BPA did not deliver useful concentrations of boron to a mammary adenocarcinoma in Hale-Stoner mice. These results, along with the selectivity of the Harding-Passey melanoma for the L isomer of BPA, are consistent with our working hypothesis that BPA is actively transported into the melanomas as an analogue of natural melanin precursors.

Animals↗
PubMed1987

Pertussis toxin blocks the inhibitory effects of calcitonin on cyclic AMP accumulation in stimulated cultured human monocytes.

Surface stimulation of fresh or cultured human mononuclear cells by latex particles causes an increase in the accumulation of cyclic AMP that is inhibited by preincubation with calcitonin (CT). Preincubation of cultured monocytes with 500 ng/ml pertussis toxin totally blocks the inhibitory effects of CT at low concentrations of this hormone. The effects of pertussis toxin are dose-related and eliminated by boiling the toxin. Similar preincubations with cholera toxin have no significant effects on subsequent inhibition of surface-stimulated cyclic AMP by CT. Membranes prepared from cultured human monocytes contain a 41,000-dalton protein that is ADP-ribosylated by pertussis toxin and may be the inhibitory guanine nucleotide regulatory protein (Ni) mediating this inhibition.

Adenosine Diphosphate Ribose↗
PubMed1986

Iodothiouracil as a melanoma localizing agent.

Thiouracil and various derivatives are selectively incorporated into the melanin pigment of melanomas during biosynthesis by serving as false melanin precursors. Using the transplantable Harding-Passey melanoma carried in BALB/c mice, we have extended our previous studies with sulfur-35 (35S) thiouracil. The persistence of high levels of [35S]thiouracil in tumor for periods of up to 2 wk has been demonstrated; during this time the drug content in normal tissues returned to near background levels. The variety of iodine isotopes available makes iodothiouracil a particularly promising melanoma-localizing agent. Tumor uptake and biodistribution of [35S]thiouracil and iodothiouracil (both iodine-127 (127I) and iodine-125 (125I) labeled) have been compared and were found to be essentially the same. The selectivity of [125I]thiouracil for melanoma has been qualitatively demonstrated by autoradiography of whole-body sections and quantitated by analysis of tumor and selected tissues. Iodothiouracil was also shown to localize in remote secondary metastases using a metastatic variant of the Harding-Passey melanoma currently being developed in our laboratory. These studies confirm the melanoma localizing capabilities of an iodinated thiouracil, and therefore the potential of using iodinated thiouracil derivatives for diagnosis and therapy of melanotic melanomas.

Animals↗
PubMed1985

Selection and properties of Leishmania tropica resistant to 10-propargyl-5,8-dideazafolate, an inhibitor of thymidylate synthetase.

Leishmania tropica promastigotes have been selected which are highly resistant to the thymidylate synthetase (TS) inhibitor, 10-propargyl-5,8-dideazafolate (CB3717). As reported for L. tropica resistant to methotrexate (MTX), an inhibitor of dihydrofolate reductase (DHFR), CB3717-resistant organisms have high levels of the bifunctional TS-DHFR and amplified DNA sequences. TS-DHFR represents up to 2% of the protein in cell extracts and does not appear to have a structural alteration that contributes to drug resistance. The amplified unit of DNA has a uniform restriction-site map throughout the selection and is nearly identical to the 30 kb amplified unit of R-region DNA found in MTX-resistant cells, except for a small increase in size of the fragment that contains a junction believed to be the site of DNA rearrangements generated during amplification. CB3717-resistant cells do not possess the amplified H-region DNA found in MTX-resistant cells. The amplified DNA in cells resistant to low levels of CB3717 appears as a 30-kb extrachromosomal circle, similar to the amplified DNA of MTX-resistant organisms. In cells resistant to higher levels of drug, the amplified DNA appeared as higher molecular weight forms. When resistant cells were grown in the absence of drug, the amplified DNA and levels of TS-DHFR gradually fell to approximately 10% of the resistant levels. These findings support the proposal that the R-region DNA possesses the sequences that encode the bifunctional protein.

Animals↗
PubMed1985

Effects of a short course of estrogen on mineral metabolism in postmenopausal women.

Previous studies suggested that estrogen administration leads to an increase in circulating immunoreactive PTH (iPTH), thought to be secondary to a slight decrease in serum calcium resulting from inhibition of bone resorption. Using three different RIAs, we measured iPTH in serum from 10 postmenopausal women before and after 14 days of ethinyl estradiol administration. In 2 sensitive RIAs directed at the midregion of the PTH molecule, iPTH values fell or remained unchanged in each subject, with average decreases of 23% (P less than 0.001) and 28% (P less than 0.005) in the two assays. Total urinary cAMP, the tubular maximum for urinary phosphate excretion, and serum iPTH measured with the third RIA did not change after estrogen treatment. Fasting urinary calcium and hydroxyproline and serum calcium, phosphorus, albumin, alkaline phosphatase, and osteocalcin all decreased after treatment, and serum 1,25-dihydroxyvitamin D increased in each subject. In a second cohort of 5 women given ethinyl estradiol for 8 weeks, similar changes were found at 2 weeks, but there was a trend toward increasing serum iPTH, increasing total urinary cAMP excretion, and decreasing the tubular maximum for urinary phosphate excretion by 8 weeks. The increase in serum 1,25-dihydroxyvitamin D and the decrease in serum osteocalcin were again found after 2 weeks of estrogen and did not change further despite continued treatment. These results indicate multiple effects of a 2-week course of estrogen treatment on mineral metabolism in the absence of an increase in serum iPTH or several biological indices of PTH activity.

Adult↗
PubMed1984

Calcitonin enhances production of prostaglandins by stimulated human monocytes.

Stimulated monocytes produce prostaglandins that may play a role in bone resorption. We studied the effects of salmon calcitonin (sCT) on human monocyte production of various prostaglandin metabolites. Latex particle-stimulated human monocyte production of prostaglandin E2, thromboxane A2 measured as thromboxane B2, and prostacyclin measured as 6-keto-PGF1 alpha was each increased in the presence of sCT. This effect required surface stimulation, was blocked by indomethacin, was less marked with equivalent concentrations of human calcitonin, and was not seen with parathyroid hormone. Calcitonin specifically affects prostaglandin pathways in stimulated human monocytes.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Unstable DNA amplifications in methotrexate-resistant Leishmania consist of extrachromosomal circles which relocalize during stabilization.

Methotrexate-resistant Leishmania tropica contain two separate regions of DNA amplification, one encoding the bifunctional thymidylate synthetase-dihydrofolate reductase (TS-DHFR) characteristic of protozoans and the other of yet unknown function. The amplified DNAs are initially found as extrachromosomal closed circular forms, which are unstable in the absence of selection. After prolonged culture in methotrexate the amplified DNAs are found as repetitive arrays associated with the chromosomal DNA fraction after CsCl-ethidium bromide density gradient centrifugation, and are stable once selection is removed. The molecular description of gene amplification in Leishmania thus closely parallels the cytological features of gene amplification in cultured mammalian cells.

Animals↗
PubMed1984

A bifunctional thymidylate synthetase-dihydrofolate reductase in protozoa.

Thymidylate synthetase and dihydrofolate reductase exist as a bifunctional protein in a number of species of protozoa which span diverse groups of the subkingdom. The enzymes copurify upon gel filtration and on affinity chromatography columns specific for dihydrofolate reductase. The bifunctional protein has been found in species of Crithidia, Leishmania, Trypanosoma, Plasmodium, Eimeria, Tetrahymena and Euglena. For reasons unknown, neither enzyme could be detected in Entamoeba histolytica or E. invadens. Since neither enzyme has yet been found as a separate protein in protozoa, it is likely that the bifunctional protein is widespread among these primitive eukaryotes. In most cases, the apparent size of the native protein is approximately twice that of the subunit possessing thymidylate synthetase. Further, with one exception, the subunit sizes are close to the sum of the subunit sizes of the separate enzymes found in other sources.

Animals↗
PubMed1983

Oxygen chiral phosphate esters.

During the past four years, methods have been reported for the syntheses and configurational analyses of virtually any phosphate mono- and diester chiral by virtue of oxygen isotope substitution, and these techniques have already been applied to an impressive number of enzymic and chemical reactions. At present, no experimental information is available that contradicts the simplest interpretations that have been applied to the results obtained for enzymic reactions: inversion of configuration indicating a direct displacement of the leaving group by the attacking group, and retention of configuration implying the formation of a phosphorylated or nucleotidylated enzyme intermediate. However, it does seem necessary to further investigate the mechanisms of at least some of the reactions discussed in this review to ensure that the simplest interpretation is correct. For example, the caveat we have raised about the interpretation of inversions of configurations in phosphohydrolase reactions is chemically reasonable, and these reactions should be reexamined to evaluate the importance of covalent catalysis by carboxylate groups. However, for the vast majority of the enzymic reactions that have been investigated, the stereochemical approach to ascertaining whether catalysis involves the formation of covalent intermediates remains the simplest and most direct method.

Binding Sites↗
PubMed1983

Mechanism of action of 2',5-difluoro-1-arabinosyluracil.

Results are described which demonstrate that the cytotoxic action of 2',5-difluoro-1-arabinosyluracil (FFara-Ura) involves conversion to the corresponding 5'-phosphate, FFara-UMP, and subsequent inhibition of thymidylate synthetase. The evidence for this is as follows: (a) cells lacking thymidine kinase are 120-fold more resistant to FFara-Ura; (b) FFara-Ura markedly inhibits the incorporation of 2'-deoxyuridine (dUrd) into DNA with little or no effect on 2'-deoxythymidine (dThd) incorporation; (c) FFara-Ura causes changes in deoxynucleoside triphosphate pool sizes, which are characteristic of specific inhibition of dTMP synthetase. Binding and spectroscopic studies demonstrate that FFara-UMP inactivates dTMP synthetase from Lactobacillus casei in a manner analogous to that described for FdUMP. Furthermore, FFara-Ura is not a substrate for the pyrimidine phosphorylases; the significance of this finding with regard to the possible chemotherapeutic utility of FFara-Ura is discussed.

Animals↗
PubMed1983

Overproduction of a bifunctional thymidylate synthetase-dihydrofolate reductase and DNA amplification in methotrexate-resistant Leishmania tropica.

Leishmania tropica promastigotes that are highly resistant to methotrexate, a dihydrofolate reductase inhibitor, have been developed. Organisms resistant to 1 mM methotrexate have a 40-fold increase in dihydrofolate reductase which is associated with thymidylate synthetase, and they contain amplified regions of DNA that may be directly visualized on stained gels of restriction digests. The amplified DNA in these organisms is about 56 kilobases in length, has a copy number about 80-fold higher than that of wild-type organisms, and constitutes about 10% of the nuclear DNA. When the methotrexate-resistant L. tropica are propagated in drug-free medium, the dihydrofolate reductase-thymidylate synthetase protein and the amplified DNA decrease in a parallel fashion until they are indistinguishable from the levels in wild-type organisms. However, when these apparent revertants are again challenged with 1 mM methotrexate, enzyme overproduction and DNA amplification occur rapidly. As in mammalian cells, it appears that drug resistance in parasitic protozoa may be mediated by gene amplification.

Animals↗
PubMed1982

Effects of calcium-regulating hormones and drugs on human monocyte chemiluminescence.

Chemiluminescence (CL) associated with phagocytosing monocytes has been used as an index of the oxygen dependent metabolic activity of these cells. Because of the relationships between monocytes and cells involved in bone resorption, we studied the effects on human monocyte CL of hormones and drugs active in mineral metabolism. Two-hour preincubations of monocytes with human PTH-(1-34), bovine PTH, or prostaglandin E2 caused significant decreases in peak CL during phagocytosis stimulated by the addition of latex particles. Similar studies with dichloromethylene diphosphonate, ethane hydroxydiphosphonate, or salmon calcitonin (sCT) caused significant increases in CL, whereas preincubation with human CT at the same molar concentration did not. CL was also decreased after preincubations with methylprednisolone or bacterial endotoxin. The effect of bovine PTH was dose dependent to concentrations as low as 10 ng/ml, was not fully present after a shorter 1-min preincubation with the hormone, and differed in an otherwise identical system using polymorphonuclear leukocytes instead of monocytes. The production of hydrogen peroxide by phagocytosing monocytes was also significantly affected by each of the drugs and hormones. The direction and magnitude of these changes were similar to those in CL experiments, except for the effects of sCT. These studies relate the oxygen-dependent function of phagocytes to mediators of bone resorption and provide a new system for studying the effects of hormones and drugs on the cellular elements of bone and blood.

Bone Resorption↗
PubMed1980

Mechanism of the adenylate cyclase reaction. Stereochemistry of the reaction catalyzed by the enzyme from Brevibacterium liquefaciens.

Adenylate cyclase from Brevibacterium liquefaciens (ATCC 14929) catalyzes the formation of the RP-diastereomer of adenosine 3':5'-cyclic monophosphorothioate from the SP-diastereomer of adenosine-5'-(1-thiotriphosphate). The reaction catalyzed by this adenylate cyclase proceeds with inversion of configuration at phosphorus, indicating that the cyclization reaction is direct and does not involve formation of an adenylated enzyme intermediate.

Adenylyl Cyclases↗
PubMedDate not supplied

Optimization of boron and neutron delivery for neutron capture therapy.

A number of groups in the United States have received funding that will permit evaluation of the clinical efficacy of the neutron capture therapy (NCT) procedure. Various reactors are being modified to allow the construction of an epithermal neutron beam. At the Brookhaven Medical Research Reactor (BMRR), the patient irradiation facility is being modified to produce an optimized epithermal neutron beam. An 80-cm-thick A1-D2O mixture (184 g/cm2, 25% D2O by volume) is being installed in the shutter assembly. One-dimensional calculations indicate that this configuration should provide an epithermal neutron flux density of approximately 1 x 10(9) n/cm2/sec at 3 MW and a concomitant fast neutron dose rate of approximately 2 x 10(-11) rad per epithermal neutron (assuming a homogeneous A1-D2O mixture). The actual geometry will be an inhomogeneous array of D2O and A1 layers producing parameters somewhat less favorable than those listed above; experimental verification is in progress. Significant gains have recently been made in selectively targeting B to melanoma with various melanaffinic compounds, including p-boronophenylalanine, and with boronated porphyrins that may be applicable to a variety of tumors. Neutron capture radiographs have been obtained with the above compounds, and efforts have been made to quantitate boron uptake in growing and quiescent or necrotic regions of tumor via double-labeling techniques obtained with tritiated thymidine. A correlation between therapeutic efficacy and the ability to deliver boron to viable areas of tumor has been observed.

Animals↗