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Cancer Research Aug 1989The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These... (Comparative Study)
Comparative Study
The abilities of the Eli Lilly compounds LY150310, LY189332, and LY135305 to inhibit spontaneous metastasis and to increase animal survival were evaluated. These compounds represent widely varied structures and were evaluated because they have been found to inhibit thromboxane synthetase, cyclooxygenase, and thrombin activation, respectively. These biochemical processes have been proposed in the literature as targets for antimetastatic drugs. The purpose of this investigation was twofold: (a) to compare the antimetastatic activities of the Eli Lilly compounds to those of the reference antimetastatic compounds nafazatrom and RA233, and (b) to examine the correlation between inhibition of spontaneous lung metastasis and survival. Spontaneous metastasis of the Lewis lung carcinoma was used to evaluate the antimetastatic activity of the compounds. In this model 5 x 10(5) tumor cells were implanted into the gastrocnemius muscle, the primary tumor was resected on Day 14, and metastatic lung lesions were counted on Day 25. Compounds were administered every 12 h on Days 5 through 19. Nafazatrom, LY150310, LY189332, and LY135305 were found to inhibit spontaneous lung metastasis in a dose-dependent manner. The ED50 values for the respective inhibitions with these compounds were 50, 0.5, 2, and 0.35 mg/kg/day; the respective therapeutic indexes (LD50/ED50) were 7, 180, 255, and 511. To evaluate the effect of nafazatrom, LY150310, LY189332, and LY135305 on animal survival, the compounds were given at maximally antimetastatic doses of 200, 60, 20, and 6 mg/kg/day, respectively. Two dosing schedules were used: (a) on Days 5 through 19 and (b) on Day 5 until death. Neither the median survival times nor the numbers of long-term survivors were significantly changed with any of the compounds at any dosing schedule. RA233, given to a maximally tolerated dose of 200 mg/kg/day on Day 5 until death, did not inhibit lung metastasis and did not increase median survival time. Postmortem examination of animals dosed with nafazatrom, LY150310, LY189332, and LY135305 showed complete inhibition in lung lesions and the appearance of lesions in the liver, kidney, spleen, and brain. The results of this investigation show that the effect a compound has on the number of metastatic lesions in a target organ may not be predictive of its effect on survival. To successfully translate laboratory data into the clinic, survival should be considered as a predictor of a compound's potential clinical utility.
Topics: Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma; Chemical Phenomena; Chemistry; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Imidazoles; Lung Neoplasms; Mice; Mopidamol; Naphthalenes; Neoplasm Metastasis; Propylamines; Pyrazoles; Pyrazolones; Random Allocation; Tetrahydronaphthalenes
PubMed: 2743339
DOI: No ID Found -
Cancer Research Apr 1987Studies with the pyrimido-pyrimidine analogue RA 233 (Rapenton) suggest that its antimetastatic action may not be mediated entirely by inhibition of platelet function....
Studies with the pyrimido-pyrimidine analogue RA 233 (Rapenton) suggest that its antimetastatic action may not be mediated entirely by inhibition of platelet function. Little is known about its direct effects on tumor cells. We investigated the in vitro effects of RA 233 on clones MTLn3 and MTC of differing metastatic potentials, isolated from the 13762NF rat mammary adenocarcinoma. The results indicated that RA 233 is cytostatic (EC50 of approximately 140 microM and approximately 180 microM for MTLn3 and MTC cells, respectively) rather than cytotoxic by determining changes in viable cell number, thymidine uptake, and incorporation of thymidine and methionine. In both clones RA 233 inhibited cAMP-dependent phosphodiesterase activity and affected cAMP accumulation in intact cells. In contrast, clonal heterogeneity in drug-induced morphological changes, such as vacuole formation and altered organization of cytoskeletal structures, as well as increased tumor cell growth at 50 microM RA 233 was observed between clones MTLn3 and MTC. These data could explain the conflicting results obtained with RA 233 when evaluated as an antimetastatic agent.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Antimetabolites, Antineoplastic; Cell Division; Cell Line; Cell Survival; Clone Cells; Cyclic AMP; Female; Kinetics; Mammary Neoplasms, Experimental; Mopidamol; Pyrimidines; Rats
PubMed: 3028616
DOI: No ID Found -
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 -
American Journal of Veterinary Research Sep 1987The influence of RA233, an inhibitor of platelet function, on the occurrence of metastasis in 18 dogs with osteosarcomas was evaluated. At least 24 hours before surgical...
The influence of RA233, an inhibitor of platelet function, on the occurrence of metastasis in 18 dogs with osteosarcomas was evaluated. At least 24 hours before surgical removal of the primary tumor, dogs were given RA233 orally (20 mg/kg of body weight divided into 3 equal doses). Original sites of the osteosarcoma included humerus, 6 dogs; radius, 5 dogs; tibia, 3 dogs; femur, 2 dogs; maxilla, 1 dog; and mandible, 1 dog. Survival time for 13 dogs euthanatized for progression of neoplastic disease ranged from 3 months to 10 months, with a mean survival time of 5.5 months. Medication was discontinued in 1 dog because of possible adverse reaction. One dog died of disease unrelated to the tumor, and one dog was euthanatized after the surgery. Two dogs were tumor free 9 and 17 months after surgery. Seemingly, the metastasis potential was not diminished in dogs given 20 mg of RA233/kg/day.
Topics: Animals; Bone Neoplasms; Dog Diseases; Dogs; Female; Male; Mopidamol; Neoplasm Metastasis; Osteosarcoma; Pyrimidines
PubMed: 3477971
DOI: No ID Found -
The Annals of Thoracic Surgery Jan 1976Dogs subjected to a thoracotomy in which a rib-spreading retractor was employed developed filling defects in the cerebral microcirculation attributable to obstruction by...
Dogs subjected to a thoracotomy in which a rib-spreading retractor was employed developed filling defects in the cerebral microcirculation attributable to obstruction by microemboli. These changes were not observed in control groups and could be prevented in the experimental group by pretreatment with RA233, a platelet inhibitor. It is possible that microembolic-related complications of operations and trauma, such as pulmonary insufficiency, might be ameliorated by the use of platelet inhibitors.
Topics: Animals; Brain; Dogs; Intracranial Embolism and Thrombosis; Microcirculation; Mopidamol; Postoperative Complications; Pyrimidines; Thoracic Surgery; Thorax
PubMed: 1247322
DOI: 10.1016/s0003-4975(10)64885-0 -
Journal of Medicine 1980
Comparative Study
Topics: Animals; Colony-Forming Units Assay; Depression, Chemical; Epoprostenol; Granulocytes; Hematopoiesis; Leukocyte Count; Male; Mice; Mice, Inbred C57BL; Mopidamol; Pentoxifylline; Phosphodiesterase Inhibitors; Prostaglandins
PubMed: 6762405
DOI: No ID Found -
Clinical & Experimental Metastasis 1983The effect of the platelet aggregation inhibitor RA233 alone or in combination with radiation was investigated on the spontaneously metastasizing B16 melanoma and on the...
The effect of the platelet aggregation inhibitor RA233 alone or in combination with radiation was investigated on the spontaneously metastasizing B16 melanoma and on the Lewis lung carcinoma. The effect of this, agent on intravenously injected cells from these tumours was also studied. When single viable 3LL or B16 melanoma cells were injected intravenously, RA233 significantly increased the number of 3LL lung colonies but decreased significantly the B16 lung colonies. RA233 alone did not influence the number of pulmonary metastases arising spontaneously from the B16 or 3LL tumours either with the primary in situ or following excision. When lungs were irradiated before implantation of the 3LL an increase in the number of metastases resulted. This increase was unaffected by RA233 administration. When the primary B16 was irradiated 14 days after implantation and excised 7 days later, a significant decrease in numbers and distribution of metastases resulted in animals treated with RA233. This was accompanied by a considerable increase in long-term survivors.
Topics: Animals; Blood Platelets; Carcinoma; Cell Line; Combined Modality Therapy; Female; Lung; Lung Neoplasms; Melanoma; Mice; Mice, Inbred C57BL; Mopidamol; Neoplasm Metastasis; Pyrimidines
PubMed: 6543684
DOI: 10.1007/BF00118472 -
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 -
Cancer Letters Sep 1982The dissemination of malignant cells from a primary tumor to distant host sites appears to be influenced by blood platelets of the hemostatic system. Under conditions...
The dissemination of malignant cells from a primary tumor to distant host sites appears to be influenced by blood platelets of the hemostatic system. Under conditions that did not inhibit primary tumor growth, RA233 decreased both the incidence and frequency of spontaneous lung metastases by 66% and 69%, respectively. Although RA 233 effectively inhibited the formation of spontaneous metastases, oral administration of RA233 prior to and after the intravenous inoculation of 1 X 10(5) B16F10 murine melanoma cells failed to inhibit subsequent lung colony formation. These findings indicate that RA233 has antimetasttic activity, and that inhibition of platelet aggregation is not the sole determinant of this action.
Topics: Animals; Cell Division; Female; Lung Neoplasms; Melanoma; Mice; Mice, Inbred C57BL; Mopidamol; Neoplasms, Experimental; Platelet Aggregation; Pyrimidines
PubMed: 7151045
DOI: 10.1016/0304-3835(82)90004-0 -
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