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Biomedical subjects

G Tortora

Publications and source records attributed to G Tortora.

104 records · Page 6Linked to original sources
PubMed1988

Synergistic inhibition of growth of breast and colon human cancer cell lines by site-selective cyclic AMP analogues.

Our past studies on the mechanism of cyclic AMP (cAMP)-mediated control of tumor growth, using the experimental rat mammary tumor models as well as human breast cancer cell lines, indicated that the action of cAMP is mediated by the RII cAMP receptor protein, the regulatory subunit of cAMP-dependent protein kinase type II (Y. S. Cho-Chung, J. Cyclic Nucleotide Res., 6: 163, 1980). We now shown that the site-selective cAMP analogues, which are manyfold more active in binding to the cAMP receptor protein than previously studied analogues, demonstrate a potent growth inhibition of seven breast and three colon human cancer cell lines. The cAMP receptor protein has two different cAMP binding sites, and cAMP analogues that selectively bind to either one of the two binding sites are known as either site 1 selective (C-8 analogues) or site 2 selective (C-6 analogues). Nineteen site-selective analogues, C-6 and C-8 monosubstituted and C-6,-8 disubstituted, were tested for their growth regulatory effect. The majority of these analogues demonstrated an appreciable growth inhibition, with no sign of toxicity in all 10 cancer lines at micromolar concentrations. The three most potent inhibitors were 8-Cl-, N6-benzyl-, and N6-phenyl-8-thio-p-chlorophenyl-cAMP, demonstrating 50% growth inhibition at 5-25 microM concentrations (IC50). Furthermore, N6-analogues, in combination with halogen or thio derivatives of C-8 analogues, demonstrated synergistic enhancement of growth inhibition. The growth inhibition paralleled a change in cell morphology, an augmentation of the RII cAMP receptor protein, and a reduction in p21 ras protein. The growth inhibition by 8-Cl-cAMP was not due to its metabolite, 8-Cl-adenosine, since: (a) the growth inhibition by 8-Cl-cAMP was released upon cessation of treatment, whereas that by 8-Cl-adenosine was not released; (b) 8-Cl-cAMP treatment did not affect cell cycle progression, whereas 8-Cl-adenosine brought about G1 synchronization; (c) 8-Cl-cAMP treatment caused reduction of p21 ras protein, whereas 8-Cl-adenosine did not affect p21 levels; and (d) 8-Cl-adenosine was not detected in either cell extracts or medium from the cells treated with 8-Cl-cAMP for 48-72 h. Site-selective cAMP analogues thus provide a new physiological means to control the growth of breast and colon human cancer cells.

Breast Neoplasms↗
PubMed1988

Selective modulation of protein kinase isozymes by the site-selective analog 8-chloroadenosine 3',5'-cyclic monophosphate provides a biological means for control of human colon cancer cell growth.

Differential expression of type I and type II cAMP-dependent protein kinase isozymes has been linked to growth regulation and differentiation. We examined the expression of protein kinase isozymes in the LS 174T human colon cancer cell line during 8-chloroadenosine 3',5'-cyclic monophosphate (8-Cl-cAMP)-induced growth inhibition. Two species of RII (the regulatory subunit of protein kinase type II) with apparent Mr 52,000 (RII52) and Mr 56,000 (RII56) and a single species of RI (the regulatory subunit of protein kinase type I) with Mr 48,000 were identified in the cancer cells. RI and both forms of RII were covalently labeled with 8-azidoadenosine 3',5'-cyclic [32P]monophosphate, and two anti-RII antibodies that exclusively recognize either RII52 or RII56 resolved two forms of the RII receptors. 8-Cl-cAMP treatment induced a decrease of RI and an increase of both RII52 and RII56 in the cytosols of cancer cells and rapid translocation (within 10 min) of RII52 from the cytosol to nucleus. 8-Cl-cAMP caused transcriptional activation of the RII52 receptor gene and inactivation of the RI receptor gene. It also exhibited high-affinity site-1-selective binding to the purified preparations of both RII receptor proteins. Thus, differential regulation of various forms of cAMP receptor proteins is involved in 8-Cl-cAMP-induced regulation of cancer cell growth, and nuclear translocation of RII52 receptor protein appears to be an early event in such differential regulation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1988

Site-selective cAMP analogs at micromolar concentrations induce growth arrest and differentiation of acute promyelocytic, chronic myelocytic, and acute lymphocytic human leukemia cell lines.

Cyclic AMP (cAMP)-dependent protein kinase may play a role in the functional and morphological differentiation of leukemic cells. In this study, we showed that the cAMP analogs, potent activators of protein kinase recently shown to be selective for either site 1 or site 2 cAMP binding sites of protein kinase, demonstrate potent growth inhibition of acute promyelocytic, chronic myelocytic, and acute lymphocytic leukemic cell lines with no sign of toxicity. The growth inhibition accompanied monocytic differentiation in HL-60 cells and a loss of nuclear terminal deoxynucleotidyl transferase activity in Molt-4 leukemic cells. The growth inhibition also paralleled a decrease in c-myc protein and RI cAMP receptor protein. Thus, cAMP analogs selective for either site 1 or site 2 of the protein kinase appear to restore a coupling of proliferation and maturation in leukemic cells.

Cell Differentiation↗
PubMed1987

Site-selective cyclic AMP analogs provide a new approach in the control of cancer cell growth.

Site-selective cyclic AMP analogs bind to site 1 or site 2 of the known cAMP-binding sites depending on the position of substituents on the purine ring, either at C-2 and C-8 (site 1) or at C-6 (site 2). The growth inhibitory effect of such site-selective cAMP analogs used in this investigation with 15 human cancer cell lines surpassed that of analogs previously tested. The most potent analogs were 8-chloro, N6-benzyl and N6-phenyl-8-p-chlorophenylthio-cAMP. The combination of a C-8 with an N6 analog had synergistic effects. The 24 site-selective analogs tested produced growth inhibition ranging from 30 to 80% at micromolar concentrations with no sign of toxic effects. Growth inhibition was not due to a block in a specific phase of the cell cycle but paralleled a change in cell morphology, an increase of the RII cAMP receptor protein and a decrease of p21 ras protein. Since the adenosine counterpart of the 8-chloro analog produced G1 synchronization without affecting the RII and p21 ras protein levels, it is unlikely that an adenosine metabolite is involved in the analog effect. Site-selective cAMP analogs thus provide a new biological tool for control of cancer growth.

Breast Neoplasms↗
PubMed1987

1-substituted 5-dialkylaminomethyl-1,5,6,7-tetrahydroindazol-4-ones with antiinflammatory and analgesic activity.

The synthesis of 1-phenyl- and 1-methyl-5-dialkylamino-methyl-1,5,6,7-tetrahydroindazol-4-ones (III) and (IV) by Mannich reaction of the corresponding 1-substituted 1,5,6,7-tetrahydroindazol-4-ones (I) and (II) is described. Some compounds (III) showed a good antiinflammatory and analgesic activity in rats and mice, respectively. Infiltration anesthesia in mice and antiacetylcholine activity in vitro are also reported.

Acetylcholine↗
PubMed1987

Esters of N-methyl-N-(2-hydroxyethyl or 3-hydroxypropyl)-1,3,3-trimethylbicyclo [2.2.1]heptan-2-endo-amine with hypotensive activity.

The synthesis of title compounds by reaction of fenchone nitrimine with 2-aminoethanol and 3-aminopropanol, followed by stereospecific NaBH4 reduction of the resulting imines, Eschweiler-Clarke reductive methylation and esterification with aliphatic and aromatic acyl chlorides is described. Some esters showed an appreciable hypotensive activity in rats. Effects on heart rate and antiarrhythmic activity in rats, as well as infiltration anesthesia in mice, are also reported.

Anesthetics, Local↗
PubMed1986

Derivatives of 1,2,3,3-tetramethyl-2-azabicyclo-[2.2.2]octan-5-trans-ol with antiarrhythmic and other activities. VI.

The synthesis of a series of alkyl and aryl amides (IV) starting from 5-trans-(3-aminopropoxy)-N-benzyl-1,2,3,3-tetramethyl-2-azabicyclo [2.2.2] octane is described. Some of compounds (IV) showed a moderate hypotensive activity in rats and infiltration anesthesia in mice. Effects on heart rate in rats and antiarrhythmic activity in mice were practically absent.

Anesthetics, Local↗
PubMed1985

Pharmacological properties of a new non-steroidal anti-inflammatory drug: flunoxaprofen.

The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.

Animals↗
PubMed1967

Synergistic effects in sonochemical sterilization.

The synergistic effects observed during the sterilization of Bacillus subtilis var. niger ATCC 9372 by the combined action of ethylene or propylene oxide with high-intensity airborne sound waves (34.8 kc/sec) were investigated. It has been shown that the number of surviving spores deposited on paper strips decreases exponentially with the sound intensity at sample level. Reductions of the order of one-third of the time required for standard propylene oxide sterilization have been observed by using the combined action of sound waves with gaseous sterilization. At the present time, maximal synergistic effects seem to be achieved for the following experimental conditions: propylene oxide concentration, 500 to 1,000 mg/liter; acoustic intensity, 161 to 162 db; contact time, 80 min; temperature, 60 C; and relative humidity, 40%. The basic mechanism involved in sonochemical sterilization seems to be more of a physical (accelerated gas diffusion) than a chemical nature.

Bacillus subtilis↗
PubMedDate not supplied

Synergistic growth inhibition and induction of apoptosis by a novel mixed backbone antisense oligonucleotide targeting CRIPTO in combination with C225 anti-EGFR monoclonal antibody and 8-Cl-cAMP in human GEO colon cancer cells.

We have evaluated the antiproliferative effect of a novel mixed backbone antisense oligonucleotide generated against the 5'-coding region of the human CRIPTO mRNA in GEO human colon cancer cells. We have also evaluated the effects of this anti-CRIPTO antisense oligonucleotide in combination with a chimeric anti-human epidermal growth factor receptor (EGFR) monoclonal antibody (MAb C225) and with 8-Cl-cAMP, a cAMP analog that specifically inhibits type I protein kinase A (PKAI), since a functional EGFR-driven autocrine pathway is operative and PKAI is overexpessed in GEO colon cancer cells. Treatment with a single agent at low doses determined a 15-35% growth inhibition. A synergistic antiproliferative effect was observed when combinations of two agents were used with a co-operativity quotient ranging between 1.5 and 2.2. Furthermore, the combined treatment with all three drugs caused an almost complete suppression of the ability of GEO cells to form colonies in soft agar. We next evaluated whether any combination of 8-Cl-cAMP, the anti-CRIPTO antisense oligonucleotide and MAb C225 could induce programmed cell death in GEO cells. Treatment with each agent alone at all doses tested did not cause DNA fragmentation. The treatment with any combination of two agents was not able to induce apoptosis. In contrast, treatment with all three compounds determined an approximately three-fold increase in DNA fragmentation. In conclusion, the combination of selective antineoplastic agents directed against different but related key signal tranduction pathways efficiently inhibits cell growth and causes apoptosis in human colorectal cancer cells.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMedDate not supplied

Effect of thymic extract 'thymostimulin' on the incidence of infections and myelotoxicity during adjuvant chemotherapy for breast cancer.

A clinical trial was made to evaluate the effectiveness of thymostimulin (TST), a bovine thymic extract, in preventing infections in breast cancer patients treated with polychemotherapy. Fifty-one women treated with adjuvant CMF were randomly divided into two groups: 25 patients received TST plus chemotherapy and 26 patients were subjected to chemotherapy only. Periodic clinical and laboratory checks were performed for at least three months to monitor the occurrence of infections and variations in immunological parameters. Infections (mostly cystitis, conjunctivitis and stomatomucositis) were observed in 37% of the TST treated patients and in 77% of the controls. (p less than 0.005). Serum immunoglobulin concentrations in the two groups were not significantly different, while quantitative analysis of peripheral T lymphocyte subsets showed a higher incidence of decreased T4/T8 ratio in the control group (p = 0.055). Finally, there was a significantly lower incidence of myelotoxicity in the TST treated patients (p less than 0.0005). In conclusion, thymostimulin seems effective in preventing some of the commonest side effects of cancer chemotherapy.

Adult↗