Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0027651 (tumor)
685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chlorpromazine (CPZ) distribution was measured in tissues of Syrian golden hamsters bearing Greene melanoma and in BALB/c mice bearing Harding-Passey melanoma. Distribution was evaluated as a function of time (0.5 to 14 days) and as a function of single and multiple doses (up to five) of from 5 to 50 mg CPZ per kg body weight. Routes of administration (i.p., i.v., p.o.) were compared. The physiological behavior of CPZ is of interest as it is used extensively as a tranquilizing drug (Thorazine). Further, since CPZ binds to the pigment melanin, the possibility exists of using CPZ to transport diagnostic or therapeutic agents to melanoma. It was found that, at 2 days postinjection, tumor/tissue concentration ratios exceeded 10 for metabolizing organs, such as liver and 100 for "back-ground" tissues, such as blood and muscle. Absolute concentrations of CPZ in tumor exceeding 100 microgram CPZ per g tumor were obtained with both single and multiple doses. This selective high concentration in tumor would make CPZ an ideal vehicle for the transport of boron to tumor for use in neutron capture therapy via the 10B(n, alpha)7Li reaction.
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PMID:Chlorpromazine distribution in hamsters and mice bearing transplantable melanoma. 705 3

Lipophilic 5'-(alkyl phosphate) esters of 1-beta-D-arabinofuranosylcytosine (ara-C) and several N4-acyl and 3'-O-acyl-2,2'-anhydro derivatives of ara-C were synthesized as potential prodrugs of ara-C 5'-monophosphate (ara-CMP). Alkylphosphorylation of ara-C, N4-palmitoyl-ara-C, and N4-stearoyl-ara-C was achieved in a single continuous operation by allowing the nucleoside to react with POCl3 in trimethyl or triethyl phosphate and adding the appropriate anhydrous alcohol directly to the intermediate phosphorodichloridate without isolation. Similar reaction of cytidine yielded cytidine 5'-(alkyl phosphate) esters, which on treatment with myristoyl or palmitoyl chloride in the presence of boron trifluoride gave 3'-O-acyl-2,2'-anhydro-ara-C 5'-(alkyl phosphate) esters. Ara-C 5'-(n-butyl phosphate) (1b), N4-palmitoyl-ara-C 5'-(n-butyl phosphate) (1h), and 2,2'-anhydro-3'-O-palmitoyl-ara-C 5'-(n-butyl phosphate) (2h) were tested against L1210/ara-C leukemia in mice in the hope that this kinase-deficient tumor would respond to treatment with these "prephosphorylated" derivatives, but no activity was observed. Of the simple 5'-(alkyl phosphate) esters tested in culture against l1210 leukemic cells, only ara-C 5'-(glyceryl phosphate) (1g) showed toxicity comparable to ara-CMP (ID50 = 0.35 and 0.65 microM, respectively), suggesting that beta-hydroxyalkyl phosphate esters may be worthwhile to examine further as prodrugs of ara-CMP.
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PMID:Lipophilic 5'-(alkyl phosphate) esters of 1-beta-D-arabinofuranosylcytosine and its N4-acyl and 2,2'-anhydro-3'-O-acyl derivatives as potential prodrugs. 705 24

Twenty-five neonatal beagles were used for this study. Gliosarcoma was injected into the cerebral hemisphere of 7 neonatal beagles (Group I). These animals were then treated by boron neutron capture therapy. The response of the tumor to therapy was evaluated by serial CT scans and 3 times magnification of cerebral angiography. The animals were sacrificed at varying post-therapy periods for histological study. Fifteen neonatal beagles implanted gliosarcoma without therapy (Group II) and 3 normal controls without tumor (Group III) were subjected to the same follow-up studies. (Results) (1) Neonatal beagles with implanted tumor showed moderate degree of ventricular dilatation within a short period. The finding of communicating hydrocephalus was interpreted as initial growth of tumor. (2) Animals after therapy had variable cavitation in the hemisphere that had contained calcium deposit on CT. Moderate dilatation of the lateral ventricle was present without any significant midline shift and there was an area of porencephaly extending out from the right lateral ventricle on CT (Fig. 1, Case 2). Cerebral angiography demonstrated hydrocephalus with an avascular region in the right cerebral hemisphere, compatible with the previously described porencephalic cyst (Fig. 2, Case 2). (3) Three cases out of 7 showed neurological symptoms after tumor implantation (Cases 3, 5 and 6). Carotid angiography showed large temporal lobe tumor with some tumor stain and also some involvement of the right frontal lobe after therapy (Fig. 7, Case 3). In postmortem examination, there was tumor seen coating the right lateral ventricle as well as the left temporal horn. The right cerebral hemisphere was slightly smaller than the left. The left lateral ventricle was remarkably enlarged (Fig. 9). (4) Four out of 7 treated animals with injected gliosarcoma showed no evidence of tumor at postmortem examination. CT demonstrated moderate dilatation of the lateral ventricle without any significant midline shift, an area of porencephaly and definite decrease in size of the right cerebral hemisphere and calvarium (Fig. 4). (5) Fifteen neonatal beagles implanted gliosarcoma without therapy (Group II) developed symptomatic and died within two weeks. (6) Control animals showed no ventricular dilatation or other abnormalities. (7) Microscopic examinations showed no similarities between implanted gliosarcoma and human glioblastoma. (Conclusion) Serial CT scans and magnification cerebral angiography in this experimental model appear extremely helpful in following the effects of therapy and important tool for the evaluation of a tumor growth or regression.
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PMID:[Neuroradiological Evaluation of an experimentally implanted tumor into cerebral hemisphere of neonatal beagles (author's transl)]. 709 78

The possibility of achieving a therapeutically useful tissue boron distribution for boron neutron capture therapy (BNCT) of cerebral gliomas with boron loaded tumor-specific antibodies is discussed. Using a theoretical tumor-immunological model and RBE dose-depth calculations, the effects of various parameters, e.g. antibody-antigen association constant, antigen site density, number of boron atoms per antibody molecule, etc., on the advantage depth, a relative measure of the resulting radiation dose distributions, are determined. It is shown that with this model a maximum in the advantage depth as a function of the blood boron concentration occurs, the position of which is dependent on the value of the parameters used. Frequently this maximum corresponds to a blood boron-10 concentration range of between 0.1 to 0.5 microgram 10B/g blood. It is concluded that given the pharmacodynamic properties of potentially useful antibody preparations for this type of tumor therapy, advantage depths significantly greater than those obtainable with existing "blood-brain-barrier" compounds are not likely to be easily achieved.
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PMID:Boron neutron capture radiation therapy of cerebral gliomas: an analysis of the possible use of boron-loaded tumor-specific antibodies for the selective concentration of boron in gliomas. 714 13

B-decachloro-o-carborane derivatives in which one of the carbon atoms was substituted by -CH2CH2CO2H (I), -CH2CHOHCH2-O-CH2CH=CH2 (II) and -CH2CHOHCH2-O-p-C6H4NHCOOC(CH3)3 (III) were prepared from decachloro-o-carborane and the corresponding bromo (I) or epoxi (II and III) derivatives under alkaline conditions. II could be epoxidized and bound to dextran, Concanavalin A, and human IgG, with a boron content of 4.3, 4.8, and 4.9% (w/w), respectively. III could be converted to the corresponding amine and further to the isothiocyanate. Such boron derivatives could be suitable compounds for neutron capture therapy of tumors, as they are well water soluble and could be attached to tumor specific antibodies.
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PMID:B-Decachloro-o-carborane Derivatives suitable for the preparation of boron-labeled biological macromolecules. 718 93

Since Locher suggested the possibility of neutron capture therapy, a number of investigators have been making efforts to establish clinical application of this treatment. For success of this therapy one of the keys is to develop a proper boron compound with selective accumulation and high concentration in the tumor. So far, sodium mercaptoundecahydrododecaborate, Na2B12H11SH is the best candidate for this purpose with its high concentration and selectivity shown by chemical analysis. Nevertheless, histological study of boron uptake to know fine distribution in tissue is inevitable for evidence of effectiveness of clinical therapy. Cytological effects in neutron capture therapy largely depend on close association of B-10 with the tumor cell. B-10, being non-radioactive isotope, can not be used as a tracer for autoradiographical study of boron distribution in tissue. Instead, alpha particles produced by (n, alpha) reaction can be used for autoradiography which demonstrates not only location of boron in tissue but tracks by alpha particles expected to occur in actual neutron irradiation. Dielectric organic polymer has been calling attention for its ability to register heavy particles which was utilized for alpha autoradiography. Autoradiography by use of plastic film without nuclear emulsion has advantages; (1) simple procedures, (2) no darkroom needed, (3) a lower background obtainable, (4) little influence of temperature and moisture, (5) long standing material and so on. The disadvantage of this procedure is that tissue sections are easily damaged by strong alkalinity used for chemical etching. To solve this problem an overlapping histologic technique was worked out, permitting one to determine the relation of the heavy particle tracks to the intra and extracellular structures. Na2B12H11SH, a boron compound already in practical use, has been restudied by using this new technique. Autoradiograms showed favorable results with abundant alpha tracks over the tumor tissue in close relation to the cells and with very few tracks over the normal brain parenchyma. This technique is a useful means not only for further development of boron compounds but for other alpha emitters.
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PMID:[Superimposition alpha-autoradiography for basic study of neutron capture therapy (author's transl)]. 727 98

The effects of fractionating boron neutron capture therapy (BNCT) were evaluated in the intracerebral rat 9L gliosarcoma and rat spinal cord models using the Brookhaven Medical Research Reactor (BMRR) thermal neutron beam. The amino acid analog p-boronophenylalanine (BPA) was administered prior to each exposure to the thermal neutron beam. The total physical absorbed dose to the tumor during BNCT using BPA was 91% high-linear energy transfer (LET) radiation. Two tumor doses of 5.1 Gy spaced 48 h apart (n = 14) or three tumor doses of 5.2 Gy, each separated by 48 h (n = 10), produced 43 and 70% long-term (> 1 year) survivors, respectively [corrected]. The outcome of neither the two nor the three fractions of radiation was statistically different from that of the corresponding single-fraction group. In the rat spinal cord, the ED50 for radiation myelopathy (as indicated by limb paralysis within 7 months) after exposure to the thermal beam alone was 13.6 +/- 0.4 Gy. Dividing the beam-only irradiation into two or four consecutive daily fractions increased the ED50 to 14.7 +/- 0.2 Gy and 15.5 +/- 0.4 Gy, respectively. Thermal neutron irradiation in the presence of BPA resulted in an ED50 for myelopathy of 13.8 +/- 0.6 Gy after a single fraction and 14.9 +/- 0.9 Gy after two fractions. An increase in the number of fractions to four resulted in an ED50 of 14.3 +/- 0.6 Gy. The total physical absorbed dose to the blood in the vasculature of the spinal cord during BNCT using BPA was 80% high-LET radiation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparative assessment of single-dose and fractionated boron neutron capture therapy. 749 75

We described previously that 10B atoms delivered by monoclonal antibody (mAb) exerted a cytotoxic effect on AH66 cells in a dose-dependent manner upon thermal neutron irradiation in vitro. In the present study, the delivering capacity of boronated anti-(alpha-fetoprotein) (AFP) mAb to carry 10B atoms to AFP-producing tumor xenografts in nude mice was determined. Boronated mAb was prepared by conjugating 50 mM 10B compound to an anti-AFP mAb (2 mg/ml) using N-succinimidyl-3-) (2-pyridyldithio) propionate. The number of 10B atoms conjugated directly to the mAb was estimated to be 459/antibody by prompt gamma-ray spectrometry. Boron concentrations in tumor tissue obtained 12, 24, 72, and 120 h after injection of 3.0 mg 10B-conjugated anti-AFP mAb were 11.10 +/- 3.12 (SD, n = 6). 29.30 +/- 5.11, 33.02 +/- 11.8, and 12.91 +/- 5.62 ppm respectively. For control 10B-conjugated anti-dinitrophenol (DNP) mAb, the values were 9.59 +/- 0.99, 10.37 +/- 2.86, 10.00 +/- 2.95, and 8.83 +/- 4.71 ppm respectively. The concentrations in blood were less than 0.40 +/- 0.10 ppm with anti-AFP mAb and less than 0.51 +/- 0.15 ppm with anti-DNP mAb at each sampling time (12, 24, 72, and 120 h). The number of 10B atoms delivered to the tumor cells was calculated to be 0.62 x 10(9), 1.63 x 10(9), 1.84 x 10(9) and 0.72 x 10(9) at each sampling time after injection of 10B-anti-AFP mAb. The amount of 10B atoms necessary for effective boron neutron-capture therapy was estimated to be 10(9)/tumor cell. We were able to carry 1.84 x 10(9) 10B atoms to AH66 tumor cells by using 10B-anti-AFP mAb. The accumulation reached its peak 72 h after injection. These data indicated that the 10B-conjugated antitumor mAb could deliver a sufficient amount of 10B atoms to the tumor cells to induce cytotoxic effects 72 h after injection upon thermal neutron irradiation.
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PMID:A targeting model of boron neutron-capture therapy to hepatoma cells in vivo with a boronated anti-(alpha-fetoprotein) monoclonal antibody. 752 92

As the first step of a research program aimed at developing a bispecific monoclonal antibody system for the delivery of boron-rich molecules to tumor cells for boron neutron capture therapy, monoclonal antibodies (mAbs) were produced against an anionic nido-carborane derivative, 4-[7,8-dicarbadodecahydroundecaborat(-1)-7-yl]butanoic acid. Two IgG subclass mAbs, designated HAW101 and HAW102, were identified that specifically bound the anionic nido-carborane hapten, as well as a variety of other anionic nido-carborane cage derivatives. By using surface plasmon resonance technology, the affinity constants of HAW101 and HAW102 were determined to be 1.9 x 10(9) and 6.8 x 10(8) M-1, respectively. A diverse array of 7-substituted and 7,8-disubstituted anionic nido-carborane derivatives reacted with the mAb HAW101 in competition ELISA, whereas anionic closo-polyhedral boranes showed negligible binding, suggesting a role for the open nido-carborane cage structure. These results suggest that mAbs such as HAW101, which bind anionic nido-carboranes, are useful in the development of bispecific mAbs for specific targeting and enhanced boron delivery to tumor sites.
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PMID:Preparation and properties of nido-carborane-specific monoclonal antibodies for potential use in boron neutron capture therapy for cancer. 762 55

Neutron penetration in tissue is a major limitation of thermal NCT, as such much work has centered upon the epithermal neutron beam in an effort to improve this situation. Further gains in neutron flux penetration, and thus therapeutic ratios, are possible if natural water is replaced with heavy water prior to therapy. Applying MCNP to a heterogeneous ellipsoidal skull/brain model, advantage depth and therapeutic depth parameters are studied as a function of heavy water replacement for a range of tumor to blood boron ratios. Both thermal (0.025 eV) and epithermal (2-7 keV) ideal neutron beams are analyzed. Using 10B ratios in the range of documented human uptake, the thermal advantage depth improved by approximately 0.7 cm for 20% D2O replacement, however, the therapeutic depth increased by less than half this value. For the epithermal beam, both the advantage depth and the therapeutic depth increased by over 1 cm. Effects of heavy water replacement on 10B requirements to therapeutically treat the midline of the brain are also evaluated.
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PMID:The influence of heavy water on boron requirements for neutron capture therapy. 764 97


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