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Proceedings of the Society For... Dec 1984It was suggested that the antitumor effect of the interferons is based in part on their ability to stimulate increased cAMP production. We have explored the interaction...
It was suggested that the antitumor effect of the interferons is based in part on their ability to stimulate increased cAMP production. We have explored the interaction of human fibroblastic beta interferon (HFIF) with a cAMP decomposition inhibitory pyrimido-pyrimidine derivative, Mopidamole (RA-233) in cultures of neoplastic and normal cell lines. Mopidamole potentiated the growth inhibitory effect of HFIF in cultures of ES-1 malignant melanoma cells, LNCaP prostatic carcinoma cells, RT-4 transitional carcinoma cells, HT-29 colon adenocarcinoma cells and in diploid fibroblast cells.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Cell Division; Cell Line; Drug Synergism; Fibroblasts; Humans; Interferon Type I; Mopidamol; Neoplasms; Pyrimidines
PubMed: 6096878
DOI: 10.3181/00379727-177-3-rc1 -
Thrombosis and Haemostasis Feb 1984A prospective randomized trial of the effects of 2 antiplatelet aggregating drugs, dipyridamole (375 mg/d), a related substance RA 233 (1500 mg/d) and placebo,... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A prospective randomized trial of the effects of 2 antiplatelet aggregating drugs, dipyridamole (375 mg/d), a related substance RA 233 (1500 mg/d) and placebo, concomitantly with oral anticoagulants, was carried out in patients with prior valvular replacement. The study was aimed to determine effect on platelet survival time (PST) of these 2 agents. The trial sample consisted of 40 males and 15 females aged 40-70 years (average 53 years). 32 received Björk-Shiley valve in aortic position, 23 underwent mitral valve replacement: 3 with Cooley-Cutter, 11 with Lillehei-Kaster 500 and 9 with Starr-Edwards 6120 prostheses; 28 patients had aortic stenosis, 21 aortic insufficiency. All the PST measured after 3 months of treatment were within normal ranges and not different between placebo, dipyridamole or RA 233 treated subjects: averages in days were, respectively, 7.49, 7.11 and 6.88. The present study did not support the claim that modern valve prosthesis could lead to a shortened PST.
Topics: Adult; Aged; Aortic Valve; Blood Platelets; Dipyridamole; Heart Valve Prosthesis; Humans; Middle Aged; Mitral Valve; Mopidamol; Pyrimidines; Time Factors
PubMed: 6719387
DOI: No ID Found -
The Journal of Biological Chemistry Jan 1984The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a...
The cycle of protein-carboxyl methylation and demethylation was studied in intact blood platelets. Platelets rapidly incorporated L-[methyl-3H]methionine and after a delay of about 20 min, they evolved [3H]methanol. This evolution, and the amount of [3H] methanol liberated by treatment with base, was inhibited in a dose-dependent fashion by the cyclic nucleotide phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine, papaverine, dipyridamole, and RA233 (2,6-bis(diethanolamino)-4-piperidinopyrimido[5,4-d] pyrimidine). Each of these compounds increased the incorporation of [3H]methionine into platelets. The effects of RA233 were studied in more detail. Inhibition of [3H]methanol production was not potentiated by stimulators of the adenylate cyclase or the guanylate cyclase. The majority of the base-labile radioactivity was trichloroacetic acid precipitable. Thin layer chromatography of extracts of platelets incubated with L-[35S]methionine showed that RA233 did not induce a cellular accumulation of [35S]S-adenosylhomocysteine, and that it actually increased the amount of cellular [35S]S-adenosylmethionine. Discontinuous polyacrylamide gel electrophoresis at acid pH using the cationic detergent benzyldimethyl-n-hexadecylammonium chloride of platelets incubated with [3H]methionine showed incorporation of radioactivity into more than 30 protein bands, including one which co-migrates with calmodulin. The incorporation into the majority of these bands was inhibited by RA233 in a dose-dependent fashion. It is suggested that caution should be used in ascribing the pharmacological effects of known phosphodiesterase inhibitors to increases in cyclic nucleotides, because some of these effects could be due to inhibition of protein carboxyl methylation.
Topics: 1-Methyl-3-isobutylxanthine; 3',5'-Cyclic-AMP Phosphodiesterases; Blood Platelets; Dipyridamole; Humans; Hydrogen-Ion Concentration; Hydrolysis; Methionine; Mopidamol; Papaverine; Protein Methyltransferases; Protein O-Methyltransferase; S-Adenosylmethionine
PubMed: 6198323
DOI: No ID Found -
Pathologie-biologie Jan 1984A number of normal and neoplastic human cell lines in culture were studied by cell count and 3H thymidine incorporation for growth inhibitory effect by the...
A number of normal and neoplastic human cell lines in culture were studied by cell count and 3H thymidine incorporation for growth inhibitory effect by the pyrimido-pyrimidine derivative RA-233 (mopidamole). There was more inhibition when the drug was added to the culture in the lag phase than in the logarithmic growth phase. There was more inhibition (particularly at low doses) of the neoplastic cell lines than of the non-neoplastic cell lines.
Topics: Antineoplastic Agents; Cell Division; Cell Line; Humans; Mopidamol; Pyrimidines
PubMed: 6701010
DOI: No ID Found -
Arzneimittel-Forschung 1984The effects of 2,2',2",2"'-[(4-piperidinopyrimido[5,4-d]pyrimidine-2,6- diyl)dinitrilo]-tetraethanol (mopidamol, RA-233), a drug with antitumour properties, have been...
The effects of 2,2',2",2"'-[(4-piperidinopyrimido[5,4-d]pyrimidine-2,6- diyl)dinitrilo]-tetraethanol (mopidamol, RA-233), a drug with antitumour properties, have been studied on membrane transports of L 1210 cells grown in culture. The results show that mopidamol is an inhibitor of thymidine and 2-deoxyglucose transport at concentrations less than or equal to 10(-4) mol/l. The inhibitory effect on cancer cells occurs as soon as 20 s after contact with the drug. Lineweaver and Burk's plots demonstrate a non-competitive type inhibitory effect on membrane transports. In addition, thymidine incorporation in DNA is decreased in the presence of mopidamol.
Topics: Animals; Antineoplastic Agents; Cells, Cultured; Deoxy Sugars; Deoxyglucose; Kinetics; Leukemia L1210; Mice; Mopidamol; Pyrimidines; Thymidine
PubMed: 6538421
DOI: No ID Found -
Journal of Medicine 1984The antiproliferative effects of six different human interferons were examined in two human cell lines: HM7 (human melanoma cell line) and MDA-MB-231 (human breast...
The antiproliferative effects of six different human interferons were examined in two human cell lines: HM7 (human melanoma cell line) and MDA-MB-231 (human breast carcinoma cell line). A dose-response curve was developed for each interferon in which the maximum dose applied gave at least 30% growth inhibition of control values after 96-128 hours of continuous exposure. An amount of RA-233 which caused 25% growth inhibition (0.05 mg for both HM7 and MDA-MB-231 cell lines) was added to the cultures with various doses of each interferon. The inhibitory effects of RA-233 and each interferon were additive at low concentrations. In no case was a synergistic effect observed. Unlike with human fibroblast interferon, we could not show a synergistic inhibitory effect between RA 233 and any of the six different interferons on these two human epithelial tumor cell lines.
Topics: Breast Neoplasms; Cell Division; Cell Line; Drug Synergism; Humans; Interferon Type I; Interferon-gamma; Melanoma; Mopidamol; Pyrimidines
PubMed: 6436421
DOI: No ID Found -
Journal of Immunopharmacology 1984Some potent phosphodiesterase (PDE)-inhibiting dipyridamole derivatives are able to increase the primary immune response in mice immunized with sheep red blood cells...
Some potent phosphodiesterase (PDE)-inhibiting dipyridamole derivatives are able to increase the primary immune response in mice immunized with sheep red blood cells (SRBC). 10mg/kg/day of the most potent substance administered in the drinking water increased the number of plaque forming cells (PFC) in spleens of these mice by a factor of about 2 when the treatment was started after immunization. Pretreating the animals did not result in an enhancement of numbers of plaque forming cells. There was no increase in the background number of PFC.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Dipyridamole; Erythrocytes; Hemolytic Plaque Technique; Immunization; Immunoglobulin M; Male; Mice; Mice, Inbred BALB C; Mopidamol; Pyrimidines; Sheep; Spleen
PubMed: 6088639
DOI: 10.3109/08923978409026457 -
Laryngologie, Rhinologie, Otologie Dec 1983Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole... (Review)
Review
Our clinical study to prevent relapse and metastases in several sarcomas and malignant lymphomas of the head and neck region with a long-term treatment with mopidamole was initiated in 1972 because the pyrimido-pyrimidine derivative was shown to inhibit platelet aggregation in vivo and to increase significantly the circulation time of intravenously injected, 32P-labelled Ehrlich ascites tumour cells in mouse blood. The aggregation of platelets to circulating tumour cells and their subsequent adhesion to vascular endothelium in turn appeared to be part of the early stages of the metastatic process. It seems, however, that other related mechanisms are also involved in the clinical results obtained. Mopidamole, as other related derivatives, probably inhibits platelet aggregation by inhibition of PDE-induced decomposition of cAMP and may stimulate the synthesis and/or release of prostacyclin from the vessel wall which in turn activates adenylate cyclase involved in cAMP synthesis. The latter mechanism was definitely shown only for the related pyrimido-pyrimidine derivative dipyridamole, the methyl-xanthine derivative pentoxifylline and the methyl-pyrazoline derivative nafazatrom. The increase of cAMP levels by mopidamole results in an inhibition of 3H-thymidine incorporation into human neoplastic cells and a direct inhibition of its mitotic rate. The adding of mopidamole to a culture of a human promyelocytic leukemic cell line promotes a reverse transformation of the malignant cells to normal which appears to be a permanent phenotypic change. Furthermore, mopidamole was shown to diminish significantly spontaneous lung metastases in syngenic Wilms' tumor (nephroblastoma) of the rat, the C1300-neuroblastoma of the mouse and the HM-Kim mammary carcinoma of the rat.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Animals; Bencyclane; Cell Adhesion; Cells, Cultured; Dipyridamole; Humans; Lymphocytes; Mice; Mopidamol; Neoplasm Metastasis; Pentoxifylline; Phosphorus Radioisotopes; Platelet Aggregation; Pyrazoles; Pyrazolones; Pyrimidines; Rats
PubMed: 6369051
DOI: No ID Found -
Clinical & Experimental Metastasis 1983The effect of RA233 alone or in combination with radiation was investigated in vivo on the S180 sarcoma, the B16 melanoma and the Lewis lung carcinoma. The combined...
The effect of RA233 alone or in combination with radiation was investigated in vivo on the S180 sarcoma, the B16 melanoma and the Lewis lung carcinoma. The combined treatment was a significant improvement over radiation alone for the B16 and S180 tumours. RA233 alone did not influence the growth of these tumours. When the primary 3LL was irradiated, tumour size was unaffected but the number of pulmonary metastases was reduced. They were further reduced by the combination of RA233 and radiation. The number, volume and cytokinetics of the B16 cells and the 3LL cells were affected to varying degrees by RA233. The significance of these changes relative to the effects of RA233 are discussed.
Topics: Animals; Antineoplastic Agents; Cell Count; Cell Cycle; Cell Division; Combined Modality Therapy; DNA, Neoplasm; Female; In Vitro Techniques; Lung Neoplasms; Male; Melanoma; Mice; Mice, Inbred C57BL; Mopidamol; Neoplasms, Experimental; Pyrimidines; Radiotherapy Dosage; Sarcoma 180
PubMed: 6546197
DOI: 10.1007/BF00121497 -
Invasion & Metastasis 1983To examine the effect of platelet-active drugs on the spread of blood-borne tumour cells, two murine tumours, sarcoma 180 (S-180) and TLX-5 lymphoma, were selected....
To examine the effect of platelet-active drugs on the spread of blood-borne tumour cells, two murine tumours, sarcoma 180 (S-180) and TLX-5 lymphoma, were selected. Following intravenous (IV) injection into CBA mice the former elicited thrombocytopenia and formed discrete pulmonary tumours, whereas the latter failed to elicit thrombocytopenia and formed discrete tumours in all visceral organs examined except the lungs. S-180 cells were injected IV into mice pre-treated with RA233 (known to prevent thrombocytopenia and thrombus formation) and TLX-5 cells were injected IV into mice pre-treated with Corynebacterium parvum (known to induce thrombocytopenia and thrombus formation). RA233 pre-treatment did not change survival time or incidence of S-180 pulmonary tumours but did result in a higher incidence of extrapulmonary tumours and a lower tumour cell burden immediately after injection. Pre-treatment with C. parvum resulted in a higher TLX-5 tumour cell burden but not discrete tumours in the lungs. On the basis of known drug activities it is proposed that thrombocytopenia induced in these experiments is in part a reflection of thrombus formation in the lungs which influences the speed of passage of tumour cells through capillaries. In some cases this may lead to a changed anatomical distribution of tumour lesions.
Topics: Animals; Bacterial Infections; Blood Platelets; Female; Lung Neoplasms; Lymphoma; Male; Mice; Mice, Inbred CBA; Mopidamol; Neoplasm Metastasis; Neoplasm Transplantation; Neoplasms, Experimental; Propionibacterium acnes; Sarcoma 180; Thrombocytopenia; Thrombosis
PubMed: 6677619
DOI: No ID Found