Synthesis and antitumor activity of 1-beta-D-arabinofuranosylcytosine conjugates of cortisol and cortisone.
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Animals↗
Biomedical subjects
C R West
Publications and source records attributed to C R West.
Chemotherapy of nonirradiated malignant gliomas. Phase II: study of the combination of methyl-CCNU, vincristine, and procarbazine.
Twenty-eight adult patients with nonirradiated malignant gliomas of the brain were administered a combination of methyl-CCNU (130 mg/m2, p.o., day 1), vincristine (2 mg/m2, i.v., day 1) and procarbazine (100 mg/m2, p.o., days 2 to 15) (MVP), scheduled to be given at successive 6 week intervals. Nineteen (67.9%) were not responsive to MVP and 9 (32.1%) were. Of 16 who had previous partial resection of their tumors, 8 (50%) responded to MVP and 8 (50%) did not. Of 12 who had previous biopsy, only 1 (8.3%) responded. Overall 1-year survival rate for the 28 patients was 28.6%. Major side effects of MVP were leukopenia, thrombocytopenia, pulmonary emboli, and thrombophlebitis, detected mainly during the first 20 to 24 weeks of treatment.
Adult↗
Intra-arterial BCNU therapy in the treatment of metastatic brain tumor from lung carcinoma: a preliminary report.
Nine patients with intracerebral metastasis from lung carcinoma were treated with intracarotid and intravertebral artery infusion of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). Four of these patients considered definite responders showed unequivocal clinical improvement and definite decreases in the size of tumors evaluated by neurologic examination, computerized tomographic (CT) scan and radionuclide brain scan (RBS). One patient's clinical condition stabilized with doubtful improvement of diagnostic tests (probable responder). The remaining four patients had further unfavorable progression of the clinical and scan findings and were clearly nonresponders. Complications were transient and included: local pain in the eye, orbit, and occipital-nuchal area during infusion in 7 patients, focal seizure in 3 patients, mild confusion with disorientation in 2 patients, and nausea in 2 patients. Our findings suggest that intra-arterial BCNU therapy may be effective and may be used as an adjuvant to surgery and/or radiotherapy for the treatment of metastatic brain tumor from lung carcinoma.
Adult↗
Nucleoside conjugates as potential antitumor agents. 2. Synthesis and biological activity of 1-(beta-D-arabinofuranosyl)cytosine conjugates of prednisolone and prednisone.
Two of the new anticancer drugs recently synthesized in our laboratory from conjugation of ara-C2 and several corticosteroids linked through a phosphodiester bond include prednisolone- (I) and prednisone-p-ara-C (II). They were demonstrated to be enzymatically hydrolyzed to the corresponding steroid and ara-CMP and the latter was further shown to be hydrolyzed to ara-C by phosphodiesterase I, snake venom, 5'-nucleotidase, and acid phosphatase. However, the conjugates were shown to be resistant to hydrolysis by alkaline phosphatase. The activity of conjugates I and II against L1210 lymphoid leukemia in female mice (C3D2F1/J) was significantly greater than that of ara-C alone or in combination with the steroid. In fact, when the optimum dosage of 75 (mumol/kg)/day x 5 was used, the administration of ara-C alone was followed by an increased life span (ILS) of 45%. This result is similar to that previously reported. With the same equimolar doses of mixtures of ara-C and either prednisolone or prednisone, the ILS values were 40 and 44%, respectively. However, when the conjugates were used, the ILS values were 89 and 100% respectively. These findings seem promising and have provided the bases for continued study of these new compounds.
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Alterations in cortical oxygen tension during the development of ischemic cerebral edema in primates (Macaca mulatta).
With a closed head primate stroke model, acute cerebral ischemia limited to the middle cerebral artery (MCA) territory was produced by macrosphere embolization of the internal carotid artery bifurcation. Measurements of the oxygen tension (PO2) at the cerebral cortical surface were obtained by continuous on-line mass spectrometry. Percentage of dry weight and tissue sodium, potassium, and chloride concentrations from ischemic and nonischemic hemispheres were determined at various times. With this preparation, we registered the precise onset of cortical surface PO2 depletion, which showed an exponential downward trend (fast component from 0 to 5 minutes, t 1/2 = 0.8 minute, rate of change = 89% per minute; slow component from 5 to 240 minutes, t 1/2 = 285 minutes, rate of change = 0.3% per minute). After the onset of cerebral ischemia, there was an immediate fall of the cortical surface PO2 with reductions of more than 45% at 5 minutes before definite hemiparesis and electroencephalographic abnormalities were recognized. During the secondary phase from 5 to 240 minutes the cortical surface PO2 fell by only an additional 23% of the steady state. Even so, when cortical surface PO2 was maintained at this critically low level, the earliest cerebral cortical edema was evident 180 minutes after MCA occlusion. Thereafter, progressive accumulation of edema fluid in the cortex (90 to 170.8 microliters per g of tissue) and in the white matter (19 to 46.2 microliter per g of tissue) was detected by the end of 240 minutes of cerebral ischemia.
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Effects of dexamethasone on tumor-induced brain edema and its distribution in the brain of monkeys.
A human choriocarcinoma was successfully adapted to grow in the brain of monkeys (Macaca mulatta), thus providing a model of tumor-induced brain edema. Four animals were given dexamethasone (3 mg/kg/day) during 3 to 5 days after the onset of clinical signs, and the other five received no treatment for the same period. Tissue water and electrolyte content of treated and untreated animals were compared in cortex and white matter at various distances from the edge of the tumor. In untreated animals, 67.9% and 23.6% swelling was detected in adjacent and remote white matter, respectively, but only 11.8% swelling was noted in adjacent cortex. In animals treated with dexamethasone these percentages of swelling were improved to 32.4% and 11.9% in the corresponding white matter, and to 4.9% in adjacent cortex. The electrolyte changes shown in edematous brain of control animals also demonstrated significant improvement in the dexamethasone-treated group. Tissue radioactivity of 3H-dexamethasone at 60 minutes after intravenous injection was high in the periphery of tumor, adjacent cortex, and white matter, but low in the center of tumor, remote cortex, and white matter. The sites with high concentrations of dexamethasone also showed significant improvement of brain edema after dexamethasone treatment, suggesting that dexamethasone may act directly at these loci.
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Haematological correlates of phytohaemagglutinin-induced lymphocyte transformation in horses.
The purpose of these investigations was to assemble and compare data which might illustrate a functional relationship between phytohaemagglutinin-induced transformation of equine lymphocytes in vitro and the haematological profiles of the lymphocyte donors. Statistically significant correlation between transformation and a haematological parameter was taken as evidence that both may be part of a common regulatory system. There was no evidence that transformation in vitro was affected by artefactual variation in the cellular composition of the cultures. Transformational behaviour of lymphocytes in autologous plasma showed significant correlation with donors' total leucocyte, neutrophil and T cell count. Different batches of donor plasma varied in ability to support the transformation and this ability was found to correlate significantly with the total leucocyte, eosinophil, lymphocyte and T cell count of the original blood. It is concluded that previously reported variation in transformation ratios of normal equine lymphocytes is attributable to regulatory mechanisms affecting circulating blood as a whole and that helminth parasitism may be among the primary causal agents which modify the mechanism.
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An evaluation of the surgical management of melanoma of the brain.
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Adult↗
A study of the effect of environmental CO2 on experimental Wilm's tumor.
The effects of exposure of experimental murine Wilm's tumor to increased atmospheric concentrations of carbon dioxide were studied. Local tumor growth was not affected by concentrations of 76% and 55% of carbon dioxide applied for 10 and 30 minutes. There was no difference in survival of animals and weight of the tumor between the control and the experimental groups. Ten per cent of the animals treated with concentrations of 55% and 76% carbon dioxide developed metastases in contrast to 30% of metastatic growth detected in the control group. This observation, although without statistically significant difference, may lead toward further study of the carbon dioxide effect in different tumor models. Additional tumor models and different animals species will be studied.
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The 'normal range' and precision of phytohaemagglutinin-induced equine lymphocyte transformation in vitro.
Data are presented on lymphocyte transformation by phytohaemagglutinin in 20 normal horses. The logarithms of transformation ratios were found to have an approximately normal distribution, giving (for the transformation ratios themselves) a geometric mean of 23.6, a range of 1.92 to 97.3, and an estimated 95 per cent tolerance interval of 1.1 to 488. Analysis of variance on the logarithms of the transformation ratios gave a coefficient of variation of 140 per cent of the transformation ratios themselves for the variation between horses; whereas the coefficient of variation between duplicate samples was only 20 per cent, that is, small compared to the variation between horses. In addition, wide fluctuations of response of individual horses over weekly periods of measurement (comparable with the variation between the horses themselves) suggest that a single set of measurements at one time cannot be taken as evidence of abnormality in a given horse.
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A study of the effect of CO2 on experimental neuroblastoma.
The effects of high concentrations of CO2 on experimental murine neuroblastoma tumor were studied. Similar to the experience with the animal model of Wilms' tumor, the local growth of this neuroblastoma model was not affected by concentrations of 76% and 55% of CO2 applied for 10 and 30 minutes. The tumor bearing animals exposed to different CO2 concentrations tended to develop metastases more frequently than the control groups, although no change in survival was noted. Different animals and additional tumor models could be used by others to study the effects of different CO2 concentrations at different exposure times.
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Spontaneous premature birth in twin pregnancy.
Factors associated with spontaneous premature birth were investigated in 459 consecutive twin deliveries at this hospital. Low maternal age, low parity, and zygosity were significantly related to the incidence of this complication. The number of previous abortions, sex combinations and related birth order, and mode of presentation of the first twin were not related to the incidence of spontaneous premature delivery. We conclude that apart from low maternal age and low parity there are no obvious factors that would permit early identification of twin pregnancies at risk from spontaneous premature birth.
Adolescent↗
Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 1: Angio-anatomy and description of an experimental model with selective embolization of the internal carotid artery bifurcation.
Selective embolization of the internal carotid artery bifurcation (ICA bifurcation) was performed in monkeys (Macaca mulatta) to study acute regional cerebral ischemia in the middle cerebral artery (MCA) territory with minimum surgical intervention in the neck under sedated conditions. The anthropomorphic similarity in angio-anatomy of the carotid system of monkeys and the use of silastic spheres, as artificial emboli, of the critical diameter of 1.2 to 1.4 mm resulted in the overall success rate of 87% in localizing the site of embolization to the ICA bifurcation, producing ischemia in the whole middle cerebral artery territory. All the animals with ICA-bifurcation embolization had contralateral deep motor weakness and conjugate eye deviation with nystagmus toward the site of embolization. Simultaneous EEG recording showed flattening of the basic background activities over the affected MCA area and cerebral arteriograms showed definite retrograde filling of the proximally occluded MCA. Clinical recovery was observed in a few animals within two to five hours of embolization. Gross ischemic swelling in the affected MCA territory, particularly in the gray matter, became obvious in six of eight animals which were exposed to four to five hours of ischemia. The angio-anatomical study of the carotid system of this experimental animal as a background for this MCA stroke model confirmed the previous observations of other investigators that the extremely abundant leptomeningeal anastomoses would be one of the major factors leading to the variability in the clinicopathological pictures seen in the models of proximal MCA occlusion. In addition, the pre-parenchymal anastomoses in the base of brain between the medial striate arteries from the proximal anterior cerebral (ACA) and lateral lenticulostriate arteries from the MCA were observed and described as a possible functional collateral to the basal ganglia in case of proximal MCA occlusion.
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Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 2: Effects on brain water and electrolytes in the early phase of MCA stroke.
Acute regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in monkeys (Macaca mulatta) by selective embolization of the internal carotid (ICA) bifurcation with minimum surgical intervention in the neck under sedated conditions. Two of five hours after embolization, brain water (measurement of dry weight) and tissue concentration of sodium and potassium were determined in the tissues of the sylvian cortex, putamen and subcortical white matter in the affected MCA territory. As early as three hours, initial increase in brain water was detected in the samples of the putament without noticeable change in tissue electrolytes in two of three animals. Gross ischemic swelling of the gray matter, in both the sylvian cortex and putamen, became obvious in six of eight animals after four to five hours. This swollen gray matter showed marked increase in brain water (up to 36% swelling), increase in tissue sodium (up to 100% of the control value), and decrease in tissue potassium (down to 55%). On the other hand, edema in the white matter, if present at all, was minimal without detectable change in tissue electrolytes and was always accompanied by much greater ( greater than two to seven times) edema in the gray matter. Thus, the gray matter edema, in both the deep subcortical structures and the cortex, appeared to play the major role in the development of hemispheric swelling of the brain which may begin within hours of the onset of the MCA stroke in monkeys. Microscopically, the swollen gray matter which showed more than 10% swelling with a definite shift of tissue sodium and potassium content appeared to be dead tissue. However, early edema in the gray matter which showed less than 10% swelling without detectable change in electrolytes might be caused by simple diffusion of water through the dysfunctional capillary wall or cell membrane with or without a permeability gradient between the intravascular cerebrospinal fluid and cerebral tissue compartment and might possibly be reversible.
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Experimental regional cerebral ischemia in the middle cerebral artery territory in primates. Part 3: effects on brain water and electrolytes in the late phase of acute MCA stroke.
Experimental regional cerebral ischemia was produced in the middle cerebral artery (MCA) territory in primates (M. mulatta) by macrosphere embolization. Determinations of percentage tissue dry weight and tissue sodium and potassium concentrations were obtained in samples from the ischemic and non-ischemic hemispheres at various time from 12 to 48 hours after the onset of cerebral ischemia. Samples from the cortex normally supplied by the occluded MCA showed maximal accumulation of edema fluid with fluxes in sodium and potassium in reciprocal directions at 12 hours and similar edematous changes in putamen at 24 hours after embolization By 48 hours after MCA occlusion and despite the presence of infarction, partial reversal was observed in the redistribution of water and electrolytes in these gray matter structures. In contrast to cerebral cortex and putamen, the adjacent subcortical white matter showed progressive increases in water content from 12 to 48 hours and definite increases in tissue sodium with decreases in potassium were not observed until 48 hours after MCA occlusion. This late severe white matter edema associated with cerebral infarction appears to be a major factor responsible for the hemispheric swelling observed at this state.
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Alterations in the distribution of water, sodium, potassium, and chloride in brain during the evolution of ischemic cerebral edema.
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