UMLS:C0027651 - FACTA Search

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Query: UMLS:C0027651 (tumor)
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The synthesis of six novel fluorinated potential prodrugs for antibody-directed enzyme prodrug therapy is described. The [2- and 3-fluoro-4-[bis(2-chloroethyl)amino]benzoyl]-L-glutamic acid (9 and 21), their bis(mesyloxy)ethyl derivatives (7 and 19), and their chloroethyl (mesyloxy)-ethyl derivatives (8 and 20) are bifunctional alkylating agents in which the activating effect of the ionized carboxyl function is masked through an amide bond to the glutamic acid residue. These compounds were designed to be activated to their corresponding benzoic acid alkylating agents at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2). The synthesis of the analogous novel parent drugs 2- and 3-fluoro-4-[bis(2-chloroethyl)amino]benzoic acid (12 and 24), their bis(mesyloxy)ethyl derivatives (10 and 22), and their chloroethyl (mesyloxy)ethyl derivatives (11 and 23) is also described. The viability of a colorectal cell line was monitored with the six potential prodrugs in the presence of CPG2 and with the parent drugs alone. Compounds 19-21 demonstrated substantial prodrug activity, with activation by CPG2 leading to cytotoxicities comparable to those of 22-24, respectively. The Km and kcat values for 7-9 and 19-21 were determined for CPG2. All potential prodrugs except 7 proved to be excellent substrates. A comparison of the relative chemical reactivity of the compounds as determined by their half-life measurements showed that the 2-fluoro substituent deactivated while the 3-fluoro substituent activated the alkylating moieties.
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PMID:Novel prodrugs of alkylating agents derived from 2-fluoro- and 3-fluorobenzoic acids for antibody-directed enzyme prodrug therapy. 805 84

Specific expression in brain astrocytes, glutamine synthetase (GS) is considered to be an indicator of cell activity, owing to its functional significance. Glutamine, its enzymic reaction product, has been found to be a precursor of nucleic acid and purine, suggesting some sort of involvement in astrocyte differentiation and proliferation. So, we conducted immunohistochemical analysis of GS in normal autopsied brain and brain tumor tissue, using anti-GS antibody. In the normal brain, GS-immunoreactivity was marked in granular form in the cerebral cortex from the second layer to sixth layers, the cerebellar granular layer, and the astrocyte bodies and projections in the Purkinje layer, but its manifestation in the cerebral white matter was extremely poor. GS was not present at all in ventricular ependymal cells and choroid plexus epithelial cells. In the primary brain tumor, GS-immunoreactivity was seen only in the astrocytoma cells. An inverse correlation between histological malignancy and degree of GS expression was observed. Otherwise, GS was expressed only in the metastatic brain tumor cells and the craniopharyngioma epithelial cells. GS expression pattern in the normal brain reflected innate function through its pronounced presence in the astrocytes, where glutamic acid-transmitting synapse were abundant. This finding together with the histological malignancy-related expression of GS in the astrocytomas suggest that it could be not only a useful marker for pathologic tumor diagnosis but also useful for evaluating the functional cataplasia of tumor-composing cells or their potential of proliferation.
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PMID:[Immunohistochemical study of glutamine synthetase expression in normal human brain and intracranial tumors]. 810 49

Classical antifolate analogues containing a novel furo[2,3-d]pyrimidine ring system which include N-[4-[N-[(2,4-diaminofuro[2,3-d]pyrimidin-5- yl)methyl]amino]benzoyl]-L-glutamic acid (1) and its N-9 methyl analogue 2 were synthesized as potential dual inhibitors of thymidylate synthase (TS) and dihydrofolate reductase (DHFR) and as antitumor agents. Four nonclassical antifolates, 2,4-diamino-5-(anilinomethyl)furo[2,3-d]pyrimidines 3-6 with 3,4,5-trimethoxy, 3,4,5-trichloro, 3,4-dichloro, and 2,5-dimethoxy substituents, respectively, in the phenyl ring, were also synthesized as potential inhibitors of DHFRs including those from Pneumocystis carinii and Toxoplasma gondii, which are organisms responsible for opportunistic infections in AIDS patients. The classical and nonclassical analogues were obtained via nucleophilic displacements of the key intermediate 2,4-diamino-5-(chloromethyl)furo[2,3-d]pyrimidine with the appropriate (p-aminobenzoyl)-L-glutamate or substituted aniline. The key intermediate was in turn synthesized from 2,4-diamino-6-hydroxypyrimidine and 1,3-dichloroacetone. The final compounds were tested in vitro against rat liver, (recombinant) human, P. carinii, T. gondii, and Lactobacillus casei DHFRs. The classical analogues showed moderate to good DHFR inhibitory activity (IC50 10(-6)-10(-8) M) with the N-CH3 analogue 2 about twice as potent as 1. The nonclassical analogues were inactive with IC50S > 3 x 10(-5) M. The classical analogues were also evaluated as inhibitors of TS (L. casei, (recombinant) human and human CCRF-CEM), glycinamide ribonucleotide formyltransferase, and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase and were found to be inactive against these enzymes. The classical analogues (particularly 2) were significantly cytotoxic toward a variety of tumor cell lines in culture. The nonclassical analogues were marginally active. Both classical compounds were good substrates for human folylpolyglutamate synthetase. Further evaluation of the cytotoxicity of 1 and 2 in CCRF-CEM cells and its sublines, having defined mechanisms of methotrexate (MTX) resistance, demonstrated that the analogues utilize the reduced folate/MTX-transport system and primarily inhibit DHFR and that poly-gamma-glutamylation was crucial to their mechanism of action. Protection studies in the FaDu squamous cell carcinoma cell line indicated that inhibition was completely reversed by leucovorin or the combination of thymidine plus hypoxanthine. Furthermore, for compounds 1 and 2, in contrast to MTX, the FaDu cells were better protected by thymidine alone than hypoxanthine alone, suggesting a predominantly antithymidylate effect.
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PMID:Classical and nonclassical furo[2,3-d]pyrimidines as novel antifolates: synthesis and biological activities. 816 59

We have previously shown that L-glutamic acid gamma-monohydroxamate (GAH) exhibits an antitumor activity, both in vitro and in vivo. In this report we explore the selective cytotoxicity of GAH in vitro by comparing the survival of tumor and normal cells. GAH exerts an irreversible delayed effect with tumoral cells and a reversible effect with normal cells: after a short incubation time of 6 hrs in the presence of 1.2 mM GAH and after removal of the drug, the survival of N Ter Dau and MRC5 cells was identical reaching about 85% after 24 hrs of culture. But, after another 48 hrs of culture, MRC5 cells recovered 100% cell survival while with N Ter Dau cells the survival decreased to 65%. A longer exposure time to GAH (18 hrs) and an additional 54 hrs of culture after removal of GAH led to 50 +/- 10% of cell survival with normal cells but only 25 +/- 10% with tumor cells. Using a long-term clonogenic assay, we showed that the 25% N Ter Dau cells surviving at 72 hrs after GAH treatment led mainly to abortive colonies (17% +/- 3%) with only 2.3 +/- 0.9% of surviving colonies. Such a difference does not exist for normal cells. Cell cycle analysis of tumor and normal cells treated with GAH (18 hrs, 1,2 mM) has shown that the drug prevents both cell type from cycling from G1 to S phase. However, the two cell types started to cycle again after removal of GAH but a delay of 24 hrs was observed for tumoral cells compared to normal cells.
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PMID:Selective cytotoxicity of L-glutamic acid gamma-monohydroxamate (GAH) for melanoma tumor cells. 823 10

Analogues of classical antifolates with the 4-aminobenzoyl group replaced by 4-amino-1-naphthoyl were synthesized for study after molecular modeling indicated ample spatial accommodation for the naphthalene ring and even larger groups in models based on reported X-ray crystallographic data describing the binding of methotrexate to human dihydrofolate reductase (DHFR). The side-chain precursors, N-(4-amino- and 4-(methylamino)-1-naphthoyl)-L-glutamic acid diethyl esters, were synthesized, and the 2,4-diamino-substituted heterocyclic groups were attached using several methods. Target compounds included naphthoyl analogues of aminopterin (AMT), methotrexate (MTX), 5-deazaAMT, 5-deazaMTX, 5-methyl-5-deazaAMT, 5-methyl-5-deazaMTX, and 5,8-dideazaAMT. A 5,6,7,8-tetrahydronaphthoyl analogue of 5-deazaAMT was also prepared. None of the naphthoyl analogues showed loss in binding to DHFR compared with the corresponding antifolate bearing the benzoyl group, thus confirming the anticipated bulk tolerance. Only the 5,6,7,8-tetrahydronaphthoyl analogue displayed reduced antifolate effects. Substrate activity toward folylpolyglutamate synthetase was, however, severely compromised. The naphthoyl compounds were transported into L1210 cells 3-6 times more readily than MTX, and despite apparently low levels of intracellular polyglutamylation, each compound was found to be significantly more potent than MTX in inhibiting tumor cell growth in vitro in three lines (L1210, HL60, and S180). The MTX, 5-methyl-5-deazaAMT, and 5-methyl-5-deazaMTX analogues were evaluated in vivo alongside MTX against E0771 mammary adenocarcinoma in mice. All three proved more effective than MTX in retarding the tumor growth. The naphthoyl analogue of 5-deazaAMT strongly inhibited DHFR from Pneumocystis carinii, Toxoplasma gondii, and rat liver giving IC50 (pM) values of 0.53, 2.1, and 1.6 respectively, but this compound did not inhibit in vitro growth of T. gondii, thus indicating lack of transport.
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PMID:Studies on analogues of classical antifolates bearing the naphthoyl group in place of benzoyl in the side chain. 827 97

1. We have established a murine hybridoma (F86) that secretes a monoclonal antibody (MoAb) specific for a 120 kDa nuclear protein (p120). p120 is expressed in all human cell lines investigated, whether of tumor or normal cell origin. 2. However, expression of p120 is significantly higher in neoplastic cells than in normal cells. The amount of p120 is relatively constant through the cell cycle and does not appear to be modulated by 72 hr serum starvation. 3. These results suggest that p120 plays some role in nuclear events associated with neoplastic phenotypes rather than in cell proliferation. 4. In situ immunofluorescence analyses indicate that p120 is located exclusively in nuclei of interphase cells. It is not present in nucleoli. 5. During mitosis, p120 is distributed in the cytoplasm and is not associated with condensed chromosomes which, together with RNAse experiments, suggests that it may be associated with hnRNA or hnRNP particles. 6. Western blot analyses indicate that p120 consists of two molecular weight forms which differ by 2-3 kDa in reduced SDS-PAGE, and several isoelectric variants in the acidic range. 7. Fractionation studies indicate that p120 has accessible free sulfhydryl group(s) and can bind ssDNA and heparin. 8. A partial cDNA clone, encoding the carboxyl terminus of p120, was isolated from a lambda gt11 library which had been prepared from human hepatoma cells (KYN-1). 9. Sequence analysis of the open reading frame revealed two possible nuclear localization sequences and several clusters of acidic amino acid residues, including a continuous run of 11 glutamic acid residues. 10. Northern blot analyses of human hepatoma RNA revealed hybridization to three transcripts which are about 4.1, 3.6, and 0.6 kb in size. 11. Dot blot analyses show that these transcripts are about 10-fold more abundant in KYN-1 hepatoma cells than in normal liver cells.
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PMID:A tumor-associated 120 kDa nuclear protein: characterization using a monoclonal antibody and a partial cDNA clone. 844 14

Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and biological characteristics.
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PMID:Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT). 854 82

10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5, 10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxyl-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (1a) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-deazapteridines (1b and 1c, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5- methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with 1a failed as did attempted further alkylation (by EtBr) of the product derived from 1a and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the EO771 mammary adenocarcinoma in mice, 9a was less active than MTX.
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PMID:Analogues of 10-deazaaminopterin and 5-alkyl-5,10-dideazaaminopterin with the 4-substituted 1-naphthoyl group in the place of 4-substituted benzoyl. 855 35

It is possible that structural changes of the androgen receptor (AR) contribute to the insensitivity of prostatic carcinomas to endocrine therapy. We have isolated DNA from 58 human prostate tumor specimens (31 carcinomas pretreatment, 13 carcinomas after relapse to hormonal therapy, and 14 benign prostatic hyperplasia), three established human prostate carcinoma cell lines and two transplantable human prostatic carcinoma xenografts. Twelve pairs of oligonucleotide primers were used to amplify the majority of the coding region of the AR gene and the products screened for mutations using single-strand conformation polymorphism (SSCP) techniques. In one tumor sample a cytosine to guanine transition in exon F which leads to substitution of glutamic acid for the wild type glutamine at position 798 of the ligand binding domain was detected. The same mutation was also found in the patient's genomic DNA and as been described in a patient with partial androgen insensitivity syndrome. Intronic mutations were detected in two of the benign prostatic hyperplasia samples, and a silent mutation at nucleotide 995 was found to be present in eight poorly differentiated carcinomas, one BPH specimen, as well as in the cell line DU145 (18% of the samples studied). In agreement with most of the literature, these studies indicate that AR mutations are rare both prior to therapy and even in androgen relapsed tumors.
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PMID:Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation polymorphism analysis. 862 19

The amino-terminal fragment of human uPA (ATF; amino acids 1-135), which contains the binding site for the uPA receptor (uPAR, CD87) was expressed in the yeast Saccharomyces cerevisiae. Recombinant yeast ATF, modified and extended by an amino-terminal in-frame insertion of a His6 tract, was purified from total protein extracts by nickel chelate affinity chromatography and shown to be functionally active since it efficiently competes with uPA for binding to cell-surface-associated uPAR. The ATF expression plasmid served as a template for the construction of a series of site-directed mutants in order to define those amino acids that are important for binding to uPAR. All mutant ATF proteins but one (deletion of Ser26) were expressed in a stable form (about 20-30 ng/mg total protein) and the binding capacity of each mutant was tested by a uPA-ligand binding assay employing recombinant uPAR immobilized to a microtiter plate. Each of the 11 amino acids of loop B of the binding region of uPA (amino acids 20-30) were individually substituted with alanine. Lys23, Tyr24, Phe25, IIe28, and Trp30 were important determinants for uPAR binding. A systematic alanine scan was also performed with chemically synthesized linear peptides spanning amino acids 14-32 of ATF. Comparable results to those with the yeast ATF mutants were obtained. In a different set of experiments, those amino acids of the uPAR-binding region of uPA that are only conserved between man and baboon but not in other species were altered: whereas substitution of Thr18 by alanine or Asn32 by serine had hardly any effect, replacement of Asn22 by tyrosine and Trp30 by arginine (both positions are strictly conserved in other mammals) led to ATF variants incapable of interacting with human uPAR. Deletion of either Val20, Ser21, Lys23, His29 or Val20 plus Ser21, respectively, also generated non-reactive ATF mutants. Finally, Lys23 in ATF was substituted with certain amino acids: whereas the replacement of Lys23 by alanine, histidine or glutamine generated ATF variants with moderate uPAR-binding activity, the introduction of a negatively charged amino acid (exchange of Lys23 by glutamic acid) completely abolished uPAR-binding activity. The results presented for the ATF mutants and uPA-derived peptides may provide clues necessary to establish the nature of the physical interaction of uPA with its receptor and may help to develop uPA-derived peptide analogues as potential therapeutic agents to block tumor cell-associated uPA/uPAR interaction.
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PMID:Systematic mutational analysis of the receptor-binding region of the human urokinase-type plasminogen activator. 864 21

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