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)

Iodine-131 3F8, a murine IgG3 monoclonal antibody that targets to GD2-bearing tumors, was administered intravenously to 12 patients with brain tumors. Six patients received 2 mCi (0.74 Bq) of 131I-3F8, five patients 10 mCi (3.7 Bq)/1.73 m2 of 131I-3F8, and one patient 2.6 mCi (0.96 Bq) of 124I-3F8, with no side-effects. Nine of 11 malignant gliomas and the single metastatic melanoma showed antibody localization, with the best tumor delineation on single-photon emission tomography (SPET) following 10 mCi (3.7 Bq)/1.73 m2 dose. No nonspecific uptake in the normal craniospinal axis was detected. There was no difference in the pharmacokinetics of low-dose versus the higher-dose antibody groups; plasma and total-body half-lives were 18 h and 49 h, respectively. Surgical sampling and time-activity curves based on quantitative imaging showed peak uptake in high-grade glioma at 39 h, with a half-life of 62 h. Tumor uptake at time of surgery averaged 3.5 x 10(-3) %ID/g and peak activity by the conjugate view method averaged 9.2 x 10(-3) %ID/g (3.5-17.8). Mean radiation absorption dose was 3.9 rad per mCi injected (range 0.7-9.6) or 10.5 cGy/Bq (range 1.9-26). There was agreement on positive sites when immunoscintigraphy was compared with technetium-99m glucoheptonate/diethylene triamine penta-acetic acid planar imaging, thallium-201 SPET, and fluorine-18 fluorodeoxyglucose positron emission tomography. Taken together, these data suggest that quantitative estimates of antibody targeting to intracranial tumors can be made using the modified conjugate view method.
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PMID:Quantitative studies of monoclonal antibody targeting to disialoganglioside GD2 in human brain tumors. 764 50

(E)-5-(2-Iodovinyl)-2'-deoxyuridine (IVDU), its 2'-fluoro-substituted derivatives IVFRU (with fluorine in the ribo configuration), IVFAU (with fluorine in the ara configuration), and the corresponding 3'-chemical delivery system (CDS), or 3'-O-(1-methyl-1,4-dihydropyridyl-3-carbonyl)- substituted derivatives IVDU-CDS, IVFRU-CDS and IVFAU-CDS were evaluated for their cytostatic activity against wild-type (FM3A/O), thymidine kinase (TK)-deficient (FM3A/TK-), and herpes simplex virus type 1 (HSV-1) or HSV-2 thymidine kinase (tk) gene-transfected murine mammary carcinoma FM3A cells (FM3A TK-/HSV-1 TK+ and FM3A TK-/HSV-2 TK+). The test compounds proved highly inhibitory to the proliferation of HSVtk gene-transfected FM3A cells. Their cytostatic activity was within the 0.002 to 0.80 microM range, a compound concentration that is 1000- to 10,000-fold lower than that required to inhibit proliferation of wild-type FM3A/O cells. The target for the cytostatic activity of the test compounds is the cellular thymidylate synthase. In contrast to the parent IVDU compound, IVFRU and IVFAU and their CDS-substituted derivatives proved resistant to phosphorolytic cleavage by human and bacterial thymidine phosphorylase and should be considered as promising candidate compounds for further evaluation for combined gene/chemotherapy of HSVtk gene-transfected tumor cells in animal models.
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PMID:Novel (E)-5-(2-iodovinyl)-2'-deoxyuridine derivatives as potential cytostatic agents against herpes simplex virus thymidine kinase gene transfected tumors. 767 Nov 7

In order to understand the structural features that might lead to an estrogen receptor (ER) based breast tumor imaging agent with improved uptake characteristics, we have synthesized several new analogs of 16 beta-fluoroestradiol (beta FES) and studied their tissue distribution in immature rats. The compounds we prepared were 11 beta-methoxy-beta FES (7a), 11 beta-ethyl-beta FES (7b), 17 alpha-ethynyl-beta FES (8c), 17 alpha-ethynyl-11 beta-methoxy-beta FES (8a), and 11 beta-ethyl-17 alpha-ethynyl-beta FES (8b). All of the analogs exhibit good affinity for ER, ranging at 25 degrees C from 10 to 460, with estradiol equal to 100. Measurement of their octanol/water partition coefficients by an HPLC method allowed us to estimate their level of nonspecific binding and thereby to predict their binding selectivity indices (BSI, i.e., the ratio of their ER-specific to nonspecific binding); the BSI values of three fluorine-substituted analogs exceed that of estradiol. These ligands have been labeled in the 16 beta position with fluorine-18 by the nucleophilic displacement of an alpha-disposed trifluoromethanesulfonate by [18F]fluoride ion. Reduction with lithium aluminum hydride produced the estradiol series ([18F]-7a-c), while treatment with lithium trimethylsilylacetylide afforded the ethynylated series ([18F]-8a-c). The synthesis time was 85 min for [18F]-7a-c and 120 min for [18F]-8a-c, with radiochemical yields ranging from 16 to 43%, and effective specific activities being 90-2900 Ci/mmol (3.3-107 TBq/mmol). In tissue distribution studies in immature female rats, all of the labeled analogs demonstrated ER-selective uptake in the principal target tissues, the uterus and the ovaries, and also in organs with lower titers of ER, the secondary target sites kidney, thymus, fat, and muscle. Although factors other than specific and nonspecific binding obviously affect the tissue distribution of these 16 beta-fluoroestrogens, we find that their ER-specific uptake by both the principal and the secondary target tissues correlates with their BSI values at a high level of statistical significance in most cases. The ethynylated-11 beta-methoxy analog [18F]-8a had high selectivity (uterus to blood ratio) after 3 h and exhibited the highest uterine uptake (percent injected dose/gram) of any fluorine-substituted estradiol ligand we have studied to date. This compound has been chosen for more detailed studies (to be described elsewhere), including clinical trials in human patients diagnosed with primary breast cancer.
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PMID:16 beta-([18F]fluoro)estrogens: systematic investigation of a new series of fluorine-18-labeled estrogens as potential imaging agents for estrogen-receptor-positive breast tumors. 768 51

Three analogues of thiazole-4-carboxamide adenine dinucleotide (TAD) (1-3) containing a fluorine atom at the C2' of the adenine nucleoside (in the ribo and arabino configuration) and at the C3' (in the ribo configuration) were synthesized in high yield from the corresponding 5'-monophosphates of 2'-deoxy-2'-fluoroadenosine (9), 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-adenine (17), and 3'-deoxy-3'-fluoroadenosine (14), respectively. Pure 2',3'-O-isopropylidene-tiazofurin 5'-phosphorimidazolide (8) was obtained by phosphorylation of the protected tiazofurin followed by treatment with carbonyldiimidazole and HPLC purification. Reaction of 8 with 9 in DMF-d7 (monitored by 1H and 31P NMR) afforded the desired dinucleotide 12, which after deisopropylidenation gave 1 in 82% yield. Small amounts of symmetrical dinucleotides AppA (10, 7.2%) and TRppTR (11, 8.0%) were also isolated during HPLC purification of the major product 12. In a similar manner, compounds 2 and 3 were obtained by coupling of 8 with 14 and 17 in 80% and 76% yield, respectively. All newly prepared fluoro-substituted compounds as well as beta-CF2-TAD, earlier synthesized by us, showed good inhibitory activity against inosine monophosphate dehydrogenase type II, the isozyme which is predominant in neoplastic cells. Binding of 1 (Kis = 0.5 microM), 2 (Kis = 0.7 microM), and 3 (Kis = 2.9 microM) was comparable to that of TAD (Ki = 0.2 microM). The difluoromethylene bisphosphonate analogue, beta-CF2-TAD (Ki = 0.17 microM), was found to be equally effective as the best cofactor-type inhibitor, beta-CH2-TAD (Ki = 0.11 microM). Interestingly, the level of inhibition of horse liver alcohol dehydrogenase by these compounds was found to be much lower (0.1 mM for 1 and 2 and no inhibition up to 10 mM for 3). These findings show that inhibition of tumor-induced inosine monophosphate dehydrogenase type II is selective and may be of therapeutic interest.
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PMID:Potent inhibitors of human inosine monophosphate dehydrogenase type II. Fluorine-substituted analogues of thiazole-4-carboxamide adenine dinucleotide. 770 13

We review the current therapy for melanoma. The diagnosis, prognostic variables, staging, treatment, and follow-up guidelines for cutaneous melanoma are reviewed from the earliest to the most advanced stages. New guidelines for margins are discussed. A new, evolving, innovative radiographic technique, positron emission tomography using 2-fluorine-18-fluoro-2-deoxy-D-glucose, may be useful to identify subclinical nodal and visceral disease. Recent advances with respect to tumor vaccines, gene therapy, immunotherapy, and interleukin 2 as well as current concepts regarding lymph node dissection are discussed.
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PMID:Current therapy for cutaneous melanoma. 864 8

5-Fluorouracil (5-FU) is an effective antitumor agent used in treating various cancers. Because of its metabolism by intestinal and other cells, 5-FU has an inconsistent bioavailability that limits its oral use. 5-Fluoro-2-pyrimidione (5-FP), a 5-FU prodrug, was synthesized and found to be converted to 5-FU by aldehyde oxidase, an enzyme present in high concentrations in the livers of mice and humans but not in the gastrointestinal tract. Using BDF1 mice, the pharmacokinetics of 5-FP were studied and compared with those of 5-FU. The bioavailability of 5-FP given orally was 100% at a dosage of 25 mg/kg and 78% at a dosage of 50 mg/kg. The half-lives of both doses of 5-FP were at least 2-fold longer than the half-lives of the same doses of 5-FU, and the clearance rates of 5-FP were 3-fold slower. 5-FP was converted rapidly to 5-FU, in vivo. The resulting 5-FU was measured at a steady-state level of 40-70 microM in plasma, at a dosage of 25 mg/kg, that was sustained for at least 4 hr. Also, when given orally, 5-FP was shown to have potent activity against Colon 38 tumor cells and P388 leukemia cells in mice. The therapeutic index of 5-FP was similar to that of 5-FU in these mouse tumor models. The potential clinical use of 5-FP as a prodrug of 5-FU should be considered.
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PMID:5-Fluoro-2-pyrimidinone, a liver aldehyde oxidase-activated prodrug of 5-fluorouracil. 774 92

We describe the synthesis and tissue biodistribution of two 21-[fluoro-18F]progestin 16 alpha, 17 alpha-furanyl ketals, potential agents for imaging progesterone receptor (PR)-positive breast tumors in humans, using positron emission tomography. 21-Fluro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylmethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10a) and 21-fluoro-16 alpha, 17 alpha-[(R)-(1'-alpha-furylethylidene)dioxy]-19- norpregn-4-ene-3,20-dione (endo-10b) were chosen for radiochemical synthesis from a series of seven novel progestin 16 alpha, 17 alpha-(furanyldioxolanes) on the basis of their high relative binding affinity to PR (190% and 173%, respectively, relative to R5020 = 100%), their low nonspecific binding (NSB) (log P o/w = 3.87 and 4.13, respectively), and their resulting high binding selectivity indices (BSI; i.e., the ratio of their PR binding affinity to nonspecific binding). Radiochemical synthesis of these two species in high radiochemical purity and at high effective specific activity was accomplished by treatment of the corresponding diastereomerically pure 21-trifluoromethanesulfonates with fluorine-18 anion. In tissue biodistribution studies in estrogen-primed immature female Sprague-Dawley rats, both [18F]-endo-10a and [18F]endo-10b demonstrated high PR-selective uptake in the principal target tissues, the uterus and the ovaries, and relatively low uptake in fat and bone. The metabolism at the 21-position in these progestins (as monitored by in vivo defluorination) appears to be less than that in other 21-fluoroprogestins; this may reflect steric inhibition of metabolism at this site due to the bulk of the furan-substituted dioxolane ring at the 16 alpha, 17 alpha-position. Comparison with other fluorine-18-labeled progestins shows that the PR-specific uptake in uterine tissue correlates with the BSI of the ligand and that the fat uptake correlates with the NSB of the ligand at high levels of statistical significance. These two dioxolanes may prove to be useful as breast tumor-imaging agents in humans.
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PMID:Fluorine-18-labeled progestin 16 alpha, 17 alpha-dioxolanes: development of high-affinity ligands for the progesterone receptor with high in vivo target site selectivity. 783 Feb 75

The causes of tumor resistance to hepatic arterially infused fluorodeoxyuridine (FdUrd) are poorly understood. A previous study showed that sufficient arterial perfusion relative to liver is necessary for tumor response. The present study examined the effect of transport on FdUrd flux from arterial blood into tumor cells. Five patients with large intrahepatic tumors (four with colorectal hepatic metastases, one with hepatoma) were given bolus hepatic arterial (HA) injections of [18F]FdUrd, and their livers imaged dynamically with a dual-detector gamma camera. Cellular entry of [18F]FdUrd was inferred by comparison with HA-injected 99mTc diethylenetriaminepentaacetate, an extracellular indicator. The images were analyzed to determine single-pass, blood-into-cell, extraction fractions [E(FdUrd)] and fractional retention of extracted radiolabel vs. time in tumors and liver. Measured E(FdUrd) ranged from 0.75 to 0.91 (mean 0.87 +/- 0.03) in liver and from 0.56 to 0.96 (mean 0.78 +/- 0.08) in tumors. Fluorine-18 was lost from tumors and liver at similar rates following first-pass throughput of unextracted [18F]FdUrd. Less than 10% of the radiolabel remained in tumor or liver by 3.5 hr, implying that little 18F was incorporated into long-lived molecular species within tumor or liver. The observations indicate that, in many cases, limited transport significantly reduces the flux of FdUrd into the cells of intrahepatic tumors, implying that transport must be considered in efforts to increase tumor uptake of hepatic arterially infused FdUrd.
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PMID:Transport limits cellular entry of hepatic arterially injected 5-[18F]fluoro-2'-deoxyuridine in human intrahepatic tumors. 795 42

The intra-cellular distribution of eight halogen glucocorticoids was investigated by ion microscopy in two cellular varieties of cultured non-cancer cells (fibroblast 3T3) and cancer cells (human breast tumor cells MCF-7). Two types of ion microscopy helped to determine this distribution, a direct imaging ion microscope (SMI 300) with low spatial resolution, and a scanning ion microscope (IMS4F), featuring high resolution, serving to obtain maps representing the intra-cellular distribution of the fluorine elements and drugs present in these monolayer cultured cells. The fluorine images representative of the drugs containing fluorine showed that these drugs are essentially concentrated in the cell nuclei. In these nuclei, the distribution of these drugs is different from that of heterochromatin and of the nucleolus.
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PMID:Advantages of the scanning ion microscopy for mapping halogen corticoids in normal and transformed cells in culture. 798 43

The purpose of this review is to present the recent developments in the medical applications of SIMS microscopy. This technique is one of the microanalytical mass spectrometry methods which allow in theory the detection of all the elements of the Mendeleiev table as well as the separation of stable and radioactive isotopes. It is based on a phenomenon whereby a biological sample surface is sputtered by bombardment with an energetic 'primary ion' beam. Part of the sputtered matter is ionized and the resulting 'secondary ions' are characteristic of the atomic composition of the analyzed area. These secondary positive or negative ions are collected and separated in a mass spectrometer at low or high mass resolution, which is dependent on both the element studied and its concentration. An analytic image which conserves the tissue distribution of the selected element is displayed on a fluorescent screen linked to an image processing system. Local elemental concentration can also be measured. Results are highly dependent on the techniques used for sample preparation which should preserve both the chemical and the structural integrity of the tissue. Further, the ionic images must be correlated with corresponding images of the same areas of the serial sections observed in a photonic microscope. With our SIMS microscope (lateral resolution approximately 0.5 microns, and mass resolution 300 to 12,000) we have demonstrated that this microscopic imaging technique is suitable for physiopathological studies. We revisited thyroid iodine metabolism by mapping chemical elements such as 32S and 127I, characteristic of hormonal physiology. Newly organified iodine (radioiodine) can be evaluated in relation to previously stored iodine (127I) in a given follicle, thus allowing an appraisal of glandular adaptation to aging and iodine overload. Another area in which SIMS can be used in medicine, is for the localization of drug markers in tumor tissue (e.g. fluorine-5-fluouracil, iodine in iododeoxyrubicin). This could facilitate the evaluation of the intratumor drug concentration at the onset of the treatment. Likewise, SIMS can be used to localize radiopharmaceuticals used in diagnosis (e.g. technetium) and therapy (131I of metaiodobenzylguanidine). This would permit a better evaluation of the radiation dose delivered to tissue. Further prospects are within reach with the imminent advent of higher lateral resolution (0.05 microns) SIMS microscopes.
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PMID:Recent developments in medical applications of SIMS microscopy. 798 27


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