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)

A new type of antineoplastic nucleoside, 2'-deoxy-2'-methylidenecytidine (DMDC) has been synthesized from the corresponding 2'-keto pyrimidine nucleosides 3 and 8 by the Wittig reaction. During the course of the reaction, we found that an intermediate betaine could pick a proton from the excess triphenylphosphonium bromide to form the 2'-phosphonium salts 5 and 10, which could be further converted into the 2'-deoxy-2'-methylidene nucleosides 4 and 9 by treatment with sodium hydride. Various 5-substituted DMDC derivatives 19a-e,h and their uracil congeners 16a-h were also synthesized from the corresponding 5-substituted uridines 12a-f,h. Among them, DMDC as well as 2'-deoxy-2'-methylidene-5-fluorocytidine (19a) showed potent antileukemic activity against murine L1210 cells in culture. The activity of DMDC and 19a toward various human tumor cells in culture compared with 1-beta-D-arabinofuranosylcytosine and 5-fluorouracil was also examined. In vivo antitumor activity of DMDC against L1210 was also described.
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PMID:Nucleosides and nucleotides. 97. Synthesis of new broad spectrum antineoplastic nucleosides, 2'-deoxy-2'-methylidenecytidine (DMDC) and its derivatives. 199 5

Human embryo fibroblasts of common genetic origin but exhibiting a range of phenotypes from normal to aggressively tumorigenic have been used to study resistance to the cytotoxic drugs methotrexate and N-(phosphonacetyl)-L-aspartate. Measurement of the intrinsic sensitivities of these cells to the two drugs in standard survival assays, in normal fetal bovine serum, showed increasing resistance to parallel increasing tumor-igenicity. Tumor cells were totally resistant to 10 mM N-(phosphonacetyl)-L-aspartate whereas the 50% lethal dose for methotrexate for the tumor cells was 500 nM compared with 50 nM for the normal diploid parent cell line. The difference in resistance between the immortal and tumorigenic cell lines was eliminated for both methotrexate and N-(phosphonacetyl)-L-aspartate, when the experiments were repeated in the presence of dialyzed fetal bovine serum, but could be restored by the addition of either hypoxanthine (100 microM) or uridine (10 microM). This suggested an important role for the salvage pathways of purine and pyrimidine biosynthesis in the increased resistance of the more tumorigenic cell lines. The implications of these data in relation to cancer chemotherapy will be discussed.
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PMID:Decreasing sensitivity to cytotoxic agents parallels increasing tumorigenicity in human fibroblasts. 200 69

Chemical and biological studies are presented for a new series of platinum(II) antitumor agents that violate the classical structure-activity relationships established for platinum complexes. These new agents, which have demonstrated activity against murine and human tumor systems, are cis-[Pt(NH3)2(Am)Cl]+ cations, in which Am is a derivative of pyridine, pyrimidine, purine, or aniline. Members from this series block simian virus 40 DNA replication in vitro and inhibit the action of DNA polymerases at individual guanine residues in replication mapping experiments. Monoclonal antibodies that bind selectively to cisplatin lesions on calf thymus DNA were used in a competitive enzyme-linked immunosorbent assay study to show that the platinum-triamine complexes do not produce the type of intrastrand cross-links on DNA that are characteristics of cisplatin and analogues with the general formula cis-[Pt(amine)2X2]. These results indicate that cis-[Pt(NH3)2(Am)Cl]+ cations form monofunctional adducts on DNA rather than eliminate NH3 or Am to afford bifunctional lesions. This conclusion is further supported by nuclear magnetic resonance spectroscopic and enzymatic digestion analyses of the products of the reactions of these triamine complexes with d(GpG) and dG, which also reveal monofunctional binding. When cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ was allowed to stand in phosphate-buffered saline at 37 degrees C for 14 days, however, NH4+ was released and trans-[Pt(NH3)(4-Br-pyridine)Cl2] formed concomitantly. This compound was characterized by a single crystal X-ray diffraction study, the details of which are reported. The fact that trans-[Pt(NH3)(4-Br-pyridine)Cl2] displays no anticancer activity, however, indicates that its formation from cis-[Pt(NH3)2(4-Br-pyridine)Cl]+ is not a significant component of the mechanism of action of this platinum-triamine complex. Taken together, these findings indicate that the cytotoxicity of cis-[Pt(NH3)2(Am)Cl]+ complexes most likely arises from the formation of monofunctional adducts. The DNA binding properties associated with this new class of antitumor agents suggest that they may display an activity profile different from that of cisplatin and related analogues.
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PMID:Mechanistic studies of a novel class of trisubstituted platinum(II) antitumor agents. 200 70

The pyrimidine precursor orotic acid (OA) is a constituent of dairy products and therapeutic drugs. Several recent publications point towards a tumor promoting activity of OA in rat liver. An increased production of reactive oxygen has been discussed as a possible mechanism, leading to lipid peroxidation and DNA single strand breaks. In view of contradictory results, this postulated prooxidative action of OA was reexamined with new experimental techniques. Weanling Sprague-Dawley rats were fed 1% OA in different diets for 4-35 days. The NADPH-mediated lipid peroxidation in liver homogenate and microsomes was determined in vitro by analysis of low-level chemiluminescence (CL) and the strongly correlated formation of malondialdehyde (MDA). In no case did treatment with OA result in an increase of lipid peroxidation in vitro nor did such treatment enhance the generation of reactive oxygen as measured by lucigenin CL. In accordance, the total cytochrome P-450 content as well as the activity of individual P-450 isoenzymes were unchanged. Treatment with OA did not elevate the MDA content of fresh liver homogenate when butylated hydroxytoluene (BHT) was present in the test system. However, when the antioxidant was omitted, increased levels of thiobarbituric acid reactive material were found which correlated with the triglyceride content. This could explain some published data that have been taken as indication for a prooxidative action of OA. Evidence against an increased lipid peroxidation in vivo is given by the analysis of ethane exhalation. Furthermore, no increase in DNA single strand breaks by OA treatment could be observed by the alkaline elution technique. These results do not support the hypothesis of a prooxidative activity of OA. The observed reversible decrease of the GSH/GSSG ratio is assumed to result from the reduced size of the phosphopyridine nucleotide pool due to purine deficiency and an increased consumption of NADPH by the enhanced reductive degradation of pyrimidines.
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PMID:Effect of orotic acid on the generation of reactive oxygen and on lipid peroxidation in rat liver. 201 18

The 5-deaza and 5,8-dideaza analogues of N alpha-pteroyl-L-ornithine (Pter-Orn), the 5-deaza, 8-deaza, and 5,8-dideaza analogues of N alpha-(4-amino-4-deoxypteroyl)-L-ornithine (APA-Orn), and the N delta-carboxymethyl derivative of N alpha-(4-amino-4-deoxy-N10-methylpteroyl)-L-ornithine (mAPA-Orn) were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) and as inhibitors of tumor cell growth in culture. Reductive amination of 2-acetamido-6-formylpyrido[2,3-d]pyrimidine-4(3H)-one with methyl N alpha-(4-aminobenzoyl)-N delta-(benzyloxycarbonyl)-L-ornithinate followed by removal of the blocking groups afforded the 5-deaza analogue of Pter-Orn, whereas N-alkylation of methyl N alpha-(4-aminobenzoyl)-N delta-(benzyloxycarbonyl)-L-ornithinate with 2-amino-6-(bromomethyl)quinazolin-4(3H)-one and deprotection gave the corresponding 5,8-dideaza analogue. Reductive coupling of 2,4-diaminopyrido[2,3-d]pyrimidine-6-carbonitrile and 4-aminobenzoic acid followed by reaction with 95-97% formic acid yielded 4-amino-4-deoxy-5-deaza-N10-formylpteroic acid, which on condensation with methyl N delta-(benzyloxycarbonyl)-L-ornithinate and deprotection gave the 5-deaza analogue of APA-Orn. A similar sequence starting from 2,4-diamino-quinazoline-6-carbonitrile led to the corresponding 5,8-dideaza compound, whereas treatment of 2,4-diamino-pyrido[3,2-d]pyrimidine-6-methanol with phosphorus tribromide followed by condensation with methyl N alpha-(4-aminobenzoyl)-N delta-(benzyloxycarbonyl)-L-ornithinate and deprotection afforded the 8-deaza analogue. For the preparation of the N delta-carboxymethyl derivative of mAPA-Orn, N alpha-(benzyloxycarbonyl)-L-ornithine was subjected to N delta-monoalkylation with glyoxylic acid and sodium cyanoborohydride, followed by N delta-acylation with ethyl trifluoroacetate, N alpha-deprotection by hydrogenolysis, condensation with 4-amino-4-deoxy-N10-methylpteroic acid, and N delta-deprotection by gentle treatment with ammonia. The 2,4-diamino derivatives all inhibited the growth of tumor cells in culture, with IC50 values of 0.2-2 microM, and inhibited purified DHFR with IC50 values of 0.02-0.08 microM. Deletion of ring nitrogens and N delta-carboxymethylation both increased potency in the cell growth assay; however, the ornithine derivatives were less potent than aminopterin or methotrexate.
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PMID:Synthesis and in vitro biological activity of new deaza analogues of folic acid, aminopterin, and methotrexate with an L-ornithine side chain. 201 22

A total of 19 male and 21 female South American opossums (Monodelphis domestica) were exposed to 250 J/m2 ultraviolet radiation from FS-40 sunlamps (280-400 nm) three times weekly for 70 weeks. The backs of the opossums were shaved as necessary to remove hair. In order to prevent photoreactivation of ultraviolet radiation-induced pyrimidine dimers by the light-dependent photolyase enzyme of the opossum, ultraviolet radiation-exposed opossums were housed under red lights (600-800 nm). The opossum photolyase requires light in the 320-450 nm range for its activity. Twenty-nine control opossums (14 males and 15 females) were irradiated by fluorescent lights with emission spectra primarily in the visible light range (320-700 nm); these control opossums were also housed under red lights, and their backs were also shaved to remove hair. No skin tumors were observed in control opossums, while ultraviolet radiation-exposed opossums developed a variety of hyperplastic and neoplastic skin lesions on the backs and on a single ear. Hyperplastic lesions included foci of epithelial hyperplasia, dermal fibroplasia, and focal proliferation of dermal melanocytes. A total of 20 ultraviolet radiation-exposed opossums (50%) developed skin tumors, and 13 opossums (32.5%) had more than a single tumor. Epithelial tumors included 25 papillomas, four keratoacanthomas, seven carcinomas in situ, three microinvasive squamous cell carcinomas, two invasive squamous cell carcinomas, and a single basal cell tumor. Ten dermal spindle cell tumors also occurred; most of these appeared to be fibrosarcomas. Two benign melanomas and one malignant melanoma were observed.
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PMID:Ultraviolet radiation-induced skin tumors in a South American opossum (Monodelphis domestica). 201 28

Our previous studies have shown that human skin cancers occurring on sun-exposed body sites frequently contain activated Ha-ras oncogenes capable of inducing morphologic and tumorigenic transformation of NIH 3T3 cells. In this study, we analyzed human primary squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs) occurring on sun-exposed body sites for mutations in codons 12, 13, and 61 of Ha-ras, Ki-ras, and N-ras oncogenes by amplification of genomic tumor DNAs by the polymerase chain reaction, followed by dot-blot hybridization to synthetic oligonucleotide probes designed to detect single base-pair mutations. In addition to the primary human skin cancers, we also analyzed Ha-ras-positive NIH 3T3 transformants for mutations in the Ha-ras oncogene. The results indicated that all three NIH 3T3 transformants, 11 of 24 (46%) SCCs, and 5 of 16 (31%) BCCs contained mutations at the second position of Ha-ras codon 12 (GGC----GTC), predicting a glycine-to-valine amino acid substitution, whereas only 1 of 40 skin cancers (an SCC) displayed a mutation in the first position of Ki-ras codon 12 (GGT----AGT), predicting a glycine-to-serine amino acid change. In addition, three of the SCCs contained highly amplified copies of the N-ras oncogene in their genomic DNA. Interestingly, two of the SCCs containing amplified N-ras sequences also had G----T mutations in codon 12 of the Ha-ras oncogene. These studies demonstrate that mutations in codon 12 of the Ha-ras oncogene occurred at a high frequency in human skin cancers originating on sun-exposed body sites, whereas mutation in codon 12 of Ki-ras or amplification of N-ras occurred at a low frequency. Since the mutations in the Ha-ras and Ki-ras oncogenes were located opposite potential pyrimidine dimer sites (C-C), it is likely that these mutations were induced by ultraviolet radiation present in sunlight.
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PMID:Ras gene mutation and amplification in human nonmelanoma skin cancers. 206 25

UV radiation is a potent DNA damaging agent and a known inducer of skin cancer in experimental animals. There is excellent scientific evidence to indicate that most non-melanoma human skin cancers are induced by repeated exposure to sunlight. UV radiation is unique in that it induces DNA damage that differs from the lesions induced by any other carcinogen. The prevalence of skin cancer on sun-exposed body sites in individuals with the inherited disorder XP suggests that defective repair of UV-induced DNA damage can lead to cancer induction. Carcinogenesis in the skin, as elsewhere, is a multistep process in which a series of genetic and epigenetic events leads to the emergence of a clone of cells that have escaped normal growth control mechanisms. The principal candidates that are involved in these events are oncogenes and tumor suppressor genes. Oncogenes display a positive effect on transformation, whereas tumor suppressor genes have an essentially negative effect, blocking transformation. Activated ras oncogenes have been identified in human skin cancers. In most cases, the mutations in the ras oncogenes have been localized to pyrimidine-rich sequences, which indicates that these sites are probably the targets for UV-induced DNA damage and subsequent mutation and transformation. The finding that activation of ras oncogenes in benign and self-regressing keratoacanthomas in both humans and in animals indicates that they play a role in the early stages of carcinogenesis (Corominas et al., 1989; Kumar et al., 1990). Since cancers do not arise immediately after exposure to physical or chemical carcinogens, ras oncogenes must remain latent for long periods of time. Tumor growth and progression into the more malignant stages may require additional events involving activation of other oncogenes or deletion of growth suppressor genes. In addition, amplification of proto-oncogenes or other genes may also be involved in tumor induction or progression. In contrast to the few studies that implicate the involvement of oncogenes in UV carcinogenesis, the role of tumor suppressor genes in UV carcinogenesis is unknown. Since cancer-prone individuals, particularly XP patients, lack one or more repair pathways, one can speculate that DNA repair enzymes would confer susceptibility to both spontaneous and environmentally induced cancers. Another potential candidate that can function as a tumor suppressor gene is the normal c-Ha-ras gene. Spandidos and Wilkie (1988) have shown that the normal c-Ha-ras gene can suppress transformation induced by the mutated ras gene.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular mechanisms of ultraviolet radiation carcinogenesis. 208

The thymidylate synthase (TS) content of tumor tissue was assayed and the levels of 5-fluorouracil (5-Fu) in serum and tumor tissue were determined in 21 patients with cervical cancer who were treated with UFT, a fluorinated pyrimidine. Subrenal capsule assay, a predictive tumor sensitivity test, was conducted concurrently on cervical tumor samples. TS inhibition and serum and tissue 5-Fu levels widely varied between both samples. Investigation of the relationship between the tumor growth inhibition rate determined by subrenal capsule assay and the above parameters (TS inhibition, serum and tissue 5-Fu levels) showed that TS inhibition and tumor growth inhibition were well correlated (r = 0.73). This suggests that a TS inhibition assay in tumor tissue can be a useful predictive test for tumor sensitivity of fluorinated pyrimidines.
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PMID:Thymidylate synthase inhibition as a predictor of tumor sensitivity of fluorinated pyrimidines. 211 22

Several drugs, containing a halogen atom, F or Br, that are being used in antiviral or anticancer therapy, were studied for their localization in cultured cells by ion microanalysis. The association allows to reduce the exposure time to define the intracellular localization of the studied element. The topography of the cells is given by the image of the polyatomic ion 26CN-. The image of the distribution of 81Br- or 19F-, coded in another color scale, can be superimposed, giving a polychromic image of the cell, thus showing the intracellular localization of the compound. MCF-7 tumor cells were cultured in the presence of pyrimidine derivatives. 5-Bromo-2'-deoxyuridine (BUdR) and 5-trifluorothymidine (F3TdR) were localized in the nucleus, 5-fluoro-2'-deoxyuridine (FUdR) in the nucleus and only in some nucleoli. The method is simple and rapid, as compared with techniques using radiolabeled compounds, or with immunocytochemical techniques. It is possible to observe two different compounds in the same cell. It could be applied to other compounds containing a halogen atom.
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PMID:Intracellular localization of drugs in cultured tumor cells by ion microscopy and image processing. 213 17


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