Pulmonary toxicity of ABVD chemotherapy and G-CSF in Hodgkin's disease: possible synergy.
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Adult↗
Biomedical subjects
J H Matthews
Publications and source records attributed to J H Matthews.
In vitro assessment of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide, a DNA-intercalating antitumour drug with reduced sensitivity to multidrug resistance.
The successful treatment of cancer requires the identification of new drugs with novel actions. N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide dihydrochloride (DACA) is a topoisomerase II-targeted antitumour drug with curative activity against murine Lewis lung carcinoma. DACA was assessed for novel patterns of growth inhibition using normal and multidrug-resistant human cell lines. Cells were cultured in 96-well microtitre trays and tested against DACA and related topoisomerase-directed drugs, including amsacrine, etoposide and doxorubicin, and drug concentrations for 50% growth inhibition (IC50 or GI50 values) were determined. In a series of Jurkat leukaemia lines characterised as exhibiting atypical multidrug resistance, DACA was to a large extent capable of overcoming multidrug resistance exhibited towards the other topoisomerase-directed agents. DACA was also tested against the National Cancer Institute 60-tumour-specific cell-line panel (GI50 values ranging from 420 to 5,400 nM; mean, 2,100 nM) and against a series of primary cultures of surgically excised melanomas (IC50 values ranging from 60 to 1,600 nM; mean, 590 nM). DELTA values (deviations of logarithmic IC50 or GI50 values from the mean) were calculated and compared by correlation analysis. The standard deviation of DELTA values was found to be lower for DACA than for the other topoisomerase II-directed drugs amsacrine, etoposide, doxorubicin and mitozantrone in both the cell lines and the primary cultures. These lower standard deviations appear to have resulted from the reduced susceptibility of DACA to both P-glycoprotein- and topoisomerase II-mediated multidrug-resistance mechanisms occurring naturally in cell lines and primary cultures.
Acridines↗
Large granular lymphoproliferative disease associated with nephrotic syndrome, renal failure and leukoencephalopathy.
A 23-year-old black female presented with general malaise, headache, high white cell count (136 x 10(9)/L), thrombocytopenia and nephrotic syndrome. She proved to have large granular lymphoproliferative disease with a natural killer cell phenotype and without a clonal rearrangement of the T-cell receptor genes. Renal biopsy demonstrated focal segmental glomerulosclerosis (FSGS). She developed a monophasic neurological illness, and rapidly became comatose six days after the initiation of high dose prednisone therapy. Computerized tomography of the brain showed marked hypodensity of the subcortical white matter. She regained consciousness subsequently, but died six months after her initial presentation with uncontrolled lymphocytosis and renal failure. Autopsy revealed FSGS with glomerular collapse and microcystic dilatation of the renal tubules, and there was perivascular demyelination in the subcortical white matter of the brain. We speculate that lymphokines released by the natural killer cells may have played an important role in the pathogenesis of both the nephrotic syndrome and leukoencephalopathy.
Acute Disease↗
Anticancer drug sensitivity profiles of new and established melanoma cell lines.
Metastatic melanoma is notable for its resistance to chemotherapy, and methods for determining resistance in cultures would be advantageous. We investigated the chemosensitivities of seven newly derived low passage lines and eight established melanoma lines. A 96-well microculture system utilising [3H]-thymidine incorporation was used to determine IC50 values (50% inhibitory concentrations) for lomustine, mitomycin C, 4-hydroperoxycyclophosphamide, cisplatinum, 5-fluorouracil, vincristine, doxorubicin, etoposide, amsacrine and the amsacrine analogue CI-921. Cytokinetic parameters were determined using 5-bromodeoxyuridine and flow cytometry. The presence of "transport" and "atypical" multidrug resistance was investigated with an IC50 ratio method, using pairs of drugs with differing sensitivity to these multidrug resistance mechanisms. A wide range of chemosensitivity for each of the antitumor agents was observed, and a spectrum of activity was observed in each of the assays for multidrug resistance. Unexpectedly, a number of cell lines displayed coordinate sensitivity or resistance to cytotoxic agents with unrelated mechanisms of action. Resistance mechanisms apart from "transport" and "atypical" multidrug resistance may be required to account for the observed 40-fold range in overall chemosensitivity of the melanoma lines.
Antineoplastic Agents↗
Microculture-based chemosensitivity testing: a feasibility study comparing freshly explanted human melanoma cells with human melanoma cell lines.
BACKGROUND: The culture of cancer cells has many applications in chemosensitivity testing and new drug development. PURPOSE: Our goal was to adapt simple semiautomated microculture methods for testing the chemosensitivity of melanoma cells freshly recovered from patients' tumors. METHODS: Cells were cultured on a substrate of agarose and exposed continuously to cytotoxic drugs, the effects of which were measured by determining the uptake of [3H]thymidine 4-7 days later. RESULTS: Immunocytochemical staining of cells cultured with 5-bromo-2'-deoxyuridine demonstrated that tumor cells were responsible for the measured thymidine incorporation. The effects of cytotoxic drugs were calculated as logarithmic 50% inhibitory concentrations and expressed as divergences from the mean in a log-mean graph. The inhibitory effects of amsacrine, etoposide, doxorubicin, cisplatin, mitomycin C, and fluorouracil were tested. Tumors differed widely in their sensitivity to these drugs, although sensitivity to the three topoisomerase-II-directed agents was highly correlated. Cells from two non-neoplastic hematopoietic progenitor cell lines (FT and 32D) showed chemosensitivity patterns distinct from those in the melanoma cells, indicating tissue selectivity. Two established melanoma cell lines, MM-96 and FME, were tested under the same conditions and showed sensitivity typical of at least some fresh specimens. CONCLUSIONS: These results support the validity of melanoma cell lines as models of freshly resected melanoma cells. If successfully applied to other tumor types, such semiautomated approaches could find wide application in routine hospital laboratories for the chemosensitivity testing of patients' tumor cells.
Animals↗
The association of age with dosage requirement for warfarin.
Two groups of patients have been studied in order to investigate the relationship between age and the effect of oral anticoagulant therapy. The first group comprised 364 patients aged 23-89 years who showed a stable anticoagulant effect on medium- or long-term warfarin therapy; in this group the elderly subjects were found to require, on average, a lower drug dose to maintain the same degree of anticoagulation. The second group comprised 130 patients aged 15-83 years who had received an initial standard oral dose of 10 mg of warfarin. No significant difference was found in the degree of anticoagulation achieved by 16 hours. Although the maintenance dose in elderly patients is somewhat lower than in younger, the same protocols can be used for the introduction of therapy.
Administration, Oral↗
The effects of folate deficiency on thymidylate synthetase activity, deoxyuridine suppression, cell size and doubling time in a cultured human myeloid cell line.
To help understand the pathogenesis of megaloblastic anaemia, we have studied folate-deprived HL60 cells. Cells grown with no added folic acid developed macrocytosis, a prolonged doubling time, a grossly increased deoxyuridine-suppressed value, and markedly reduced thymidylate synthetase activity. Cells in medium containing 50 nmol/l added folic acid became macrocytic with similar biochemical changes, but their doubling time was only marginally prolonged. In 100 nmol/l added folic acid, there was slight macrocytosis and a normal doubling time, but marked biochemical alterations were still present. The findings demonstrate that folate deficiency causes diminished thymidylate synthetase activity and macrocytosis in human myeloid cells, but that such cells may nevertheless demonstrate no prolongation of their doubling time, indicating either that their supply of thymidine triphosphate (TTP) is sufficient, or that misincorporation of deoxyuridine triphosphate (dUTP) is occurring. This suggests that the ineffectiveness of haemopoiesis in folate deficiency may result from damage to bone marrow cells in some way other than arrest in S-phase by a reduced delivery of TTP to the DNA replication fork.
Cell Division↗
Pregnancy-associated thrombocytopenia: definition, incidence and natural history.
We have sought to clarify the definition and importance of newly diagnosed thrombocytopenia in pregnant women by establishing an appropriate reference interval for the platelet count, and by observing the outcome in a cohort of thrombocytopenic pregnant women. The mean platelet count was lower in 2,155 healthy pregnant than non-pregnant women, and varied with race, but did not fall with increasing gestation, except in Black women. 101 of approximately 2,800 women became newly thrombocytopenic during pregnancy by conventional criteria (platelets less than 150 x 10(9)/l), without an apparent cause. Using the reference intervals established during the study, however, 24 of these women would not have been regarded as thrombocytopenic. No bleeding tendency was observed in the mothers or their infants. Maternal platelet counts became normal in the postnatal period. Thrombocytopenia occurring for the first time during pregnancy may be a different condition from auto-immune thrombocytopenia, and we suggest the term 'pregnancy-associated thrombocytopenia' (PAT). PAT does not appear to be epidemic; it does not threaten the fetus, but it cannot be distinguished from auto-immune thrombocytopenia in individual cases.
Blood Platelets↗
Response of human tumor cell lines in vitro to fractionated irradiation.
The surviving fraction of human tumor cell lines after 2 Gy (SF2) varies between 0.1 and 0.8. It has been postulated that differences in inherent radiosensitivity of tumor cells are a major determinant of radiation response in vivo. Assays of inherent radiosensitivity based on acute survival are being developed as predictors of tumor response which often assume that the same inherent radiosensitivity persists throughout a fractionated treatment. We have investigated the response of 2 human tumor cell lines (A549 and MCF7) with different inherent radiosensitivities to in vitro fractionated irradiation. A549 cells had an SF2 of 0.62 and a mean inactivation dose (D) of 3.07 Gy whereas MCF7 cells had an SF2 of 0.30 and a D of 1.52 Gy. Split dose repair capacity (at equal survival levels) was less for A549 than for MCF7 cells and recovery kinetics for both cell lines were substantially longer than those of rodent cell lines. Survival after 5 fractions of 2 Gy given 12 hr apart at 37 degrees C was near to that predicted from the acute survival curve, assuming complete repair and no proliferation. Acute survival of A549 cells which survived 5 fractions of 2 Gy given 12 hr apart was similar to the acute survival of unirradiated cells. When A549 cells were incubated at 22 degrees C between 5 fractions of 2 Gy given 12 hr apart, proliferation and split dose repair were substantially inhibited. These studies support the proposals to use in vitro inherent radiosensitivity assays for the prediction of in vivo response of tumors to fractionated treatment.
Breast Neoplasms↗
Thymidylate synthesis and utilization via the de novo pathway in normal and megaloblastic human bone marrow cells.
We have measured the thymidylate synthetase activity of intact bone marrow cells using a 3H2O release assay. The mean thymidylate synthetase activity of vitamin B12- or folate-deficient megaloblastic marrow cells was reduced only in severely anaemic patients. There was a correlation between thymidylate synthetase activity and RBC in patients with megaloblastic haemopoiesis. The mean rate of incorporation into DNA of 6-3H deoxyuridine was similar in megaloblastic and normoblastic marrows. The rate of thymidylate synthesis exceeded its incorporation into DNA in all marrows, and the mean ratio between synthesis and incorporation was similar in normoblastic and megaloblastic patients, being independent of both thymidylate synthetase activity and RBC. Thus de novo thymine nucleotides were not utilized more efficiently in megaloblastic marrow cells. These data suggest that impaired thymidylate synthesis may not be the central defect in megaloblastic haemopoiesis, and that there is only a single pool of thymidine triphosphate in human bone marrow cells.
Anemia, Macrocytic↗
Deoxyuridine suppression: biochemical basis and diagnostic applications.
The deoxyuridine (dU) suppression test evolved out of investigations into the biochemical basis of the megaloblastic changes seen in vitamin B12 and folate deficiency. Although the abnormality in dU suppression which occurs in vitamin B12- or folate-deficient states is assumed to reflect impaired methylation of deoxyuridylate, there is still no direct demonstration that this is so. Furthermore, there is evidence that reactions other than the methylation of deoxyuridylate are involved in the phenomenon of dU suppression. Nevertheless, in clinical practice abnormal dU suppression serves as a sensitive index of the presence of megaloblastosis due to vitamin B12 or folate deficiency. dU suppression is also abnormal in a number of conditions other than vitamin B12 or folate deficiency, but its overall specificity in detecting tissue dysfunction due to these two deficiency states is considerably higher than that of the serum vitamin B12 or red cell folate levels. Consequently, the test enables us simply and rapidly to define those patients in whom macrocytosis is unrelated to a deficiency of vitamin B12 or folate. For these reasons, the dU suppression test has been adopted by several laboratories across the world for investigating patients with (a) possible vitamin B12 or folate deficiency, (b) macrocytosis, and (c) megaloblastic erythropoiesis. Since the dU suppression test is abnormal in transcobalamin II deficiency and in some congenital disorders of vitamin B12 and folate metabolism, it is very useful in the investigation of obscure anaemias in infancy and childhood. In addition, it has contributed to our understanding of the mechanisms underlying the myelotoxicity of certain drugs, and particularly of nitrous oxide.
Deoxyuridine↗
The deoxyuridine suppression test performed on phytohaemagglutinin-stimulated peripheral blood cells fails to reflect in vivo vitamin B12 or folate deficiency.
Because phytohaemagglutinin-stimulated lymphocytes acquire folate deficiency in vitro, we have re-examined the claim that the deoxyuridine suppression test (dU-test) based on such cells helps to diagnose megaloblastic states. dU-test results were obtained from the phytohaemagglutinin-stimulated blood cells of 77 patients at 6 concentrations of dU. 21 megaloblastic patients with cobalamin or folate deficiency did not have a mean blood dU-test result significantly higher than that of 21 normoblastic patients at any concentration of dU. Among all patients, however, there was a weak correlation between the blood and marrow dU-test results. Folic acid corrected the blood dU-test results more in the normoblastic than the megaloblastic patients, and a difference between the two groups appeared, but a large overlap persisted. Blood dU-test results tend to be higher in megaloblastic patients, but acquired folate deficiency obscures the distinction from normoblastic patients so that the test is not of diagnostic value.
Aged↗
A case of angioimmunoblastic lymphadenopathy associated with a long spontaneous remission, retrobulbar neuritis, a clonal rearrangement of the T-cell receptor gamma chain gene and an unusual marrow infiltration.
A man with angioimmunoblastic lymphadenopathy entered a spontaneous remission that lasted 18 yr, ending in retrobulbar neuritis followed by a generalized relapse. After another remission was induced by prednisolone he developed marrow infiltration with a lymphoid cell of novel surface-marker phenotype. His lymph node cells demonstrated a clonal rearrangement of the T-cell receptor gamma chain (TcR gamma) genes whereas the TcR beta genes were heterogeneously rearranged. The marrow cells did not contain the rearranged TcR gamma gene. He died of pulmonary emboli 21 yr after his original presentation. We propose a model whereby the original event was the development of a lymphoid stem cell clone with no TcR gene rearrangement. Subsequently, a sub-clone bearing the TcR gamma gene rearrangement proliferated in the lymph nodes and further heterogeneous rearrangement of the TcR beta genes occurred within this subclone. Proliferation in the marrow of the original clone finally supervened.
Adult↗
Effect of therapy with vitamin B12 and folic acid on elderly patients with low concentrations of serum vitamin B12 or erythrocyte folate but normal blood counts.
To help understand the haematological significance of the low concentrations of serum vitamin B12 and erythrocyte folate occurring in elderly patients, 17 acute admissions to a geriatric unit with a low concentration of serum vitamin B12 or erythrocyte folate but a normal blood count were treated with vitamin B12 and folic acid for 3 months. Bone marrow deoxyuridine suppression was abnormal in 3 of these 17 patients, 2 of whom also had megaloblastic change in the marrow. With treatment, the MCV fell in 13 of the 17, and the average MCV fell from 90.5 to 87.9 fl (p = 0.007), but the mean Hb did not change. Ten untreated similar patients showed no change in their MCV over the same period, but the mean Hb fell from 14.0 to 13.1 g/dl (p = 0.04). Thus the low concentrations of serum vitamin B12 or erythrocyte folate found in approximately a quarter of acutely admitted elderly patients may indicate true tissue deficiency of these vitamins, even when the blood count is normal.
Blood Cell Count↗
Cell cycle characteristics in acute nonlymphocytic leukemia.
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Acute Disease↗
Intrinsic and reflex actions of verapamil and nifedipine: assessment in normal subjects by noninvasive techniques and autonomic blockade.
To determine the intrinsic and reflex activities of calcium antagonists, 8 healthy volunteers were administered single doses of verapamil 10 mg i.v. and nifedipine 20 mg sublingually alone and during autonomic blockade (atropine 0.04 mg/kg and propranolol 0.2 mg/kg). Heart rate, PQ-time, systolic time intervals, blood pressure, and left ventricular echocardiograms were used to measure the pharmacodynamic effects, which were evaluated by multivariate analysis of variance. In general the effects of verapamil were most distinct when the 10-min infusion ended, while nifedipine acted after a latent period of 9 minutes. Both calcium antagonists given alone induced almost identical increases in heart rate and cardiac output and decreases in total peripheral resistance. Nifedipine also reduced systolic wall stress and increased fractional shortening, while verapamil prolonged systolic time intervals and PQ-time and reduced fractional shortening. During autonomic blockade, nifedipine no longer had a significant effect on these parameters. However, after the blockade verapamil led to marked decrease in heart rate, cardiac output, blood pressure and systolic wall stress; total peripheral resistance and fractional shortening were not changed, and the systolic time intervals and PQ-time were prolonged as after verapamil alone. It is concluded that both calcium antagonists stimulate distinct sympathetic reflexes, which may modify or even reverse their intrinsic actions. The effects of nifedipine on the cardiovascular system are considered to result from a reduction in peripheral vascular tone, whereas the effects of verapamil can be attributed to cardiac (negative inotropic, chronotropic and dromotropic) and peripheral vascular actions.
Adult↗
Digoxin and bepridil: pharmacokinetic and pharmacodynamic interactions.
The influence of bepridil on steady-state serum digoxin concentrations (SDCs) and the pharmacodynamic actions of both drugs were tested in 48 healthy subjects in a randomized, double-blind study. Subjects were assigned to one of two groups of 24 subjects each: One group received placebo 1, while the other received digoxin, 0.375 mg/day, loaded with doubled doses on days 1 and 2, for 14 days. After 7 days the groups were subdivided into four groups of 12 subjects each and received concurrent dosing of digoxin with either placebo 2 or bepridil, 300 mg/day, loaded with 900 mg on day 8. Mean (+/- SD) SDCs rose during concurrent bepridil dosing from 0.93 +/- 0.22 to 1.25 +/- 0.25 ng/ml (P less than 0.001). Noninvasive cardiovascular parameters from ECG, systolic time intervals, and electrical impedance cardiography were not influenced by the placebos. Digoxin and bepridil reduced heart rate and prolonged the PQ interval because of negative chronotropic and dromotropic properties. Positive inotropism from digoxin shortened the corrected electromechanical systole (QS2c) and the preejection period and increased impedance cardiography [(dZ/dt)/RZ index]; the opposite effects occurred after bepridil, indicating negative inotropism. The QT interval corrected for heart rate (QTc) showed a similar pattern of changes, as did QS2c for each drug. Concurrent dosing of both drugs resulted in an addition of their chronotropic effects, whereas the dromotropic effects of each drug alone was not intensified. The strengthened digoxin effect from the increased SDC diminished the negative inotropic effect of bepridil. Overall, drug coadministration resulted in a nearly unchanged digoxin-induced positive inotropism.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Acquired folate deficiency in phytohaemagglutinin-stimulated human lymphocytes.
3H-thymidine (3H-TdR) incorporation, deoxyuridine (dU)-suppressed values, modal cell volume and the relative DNA content of individual cells have been determined in phytohaemagglutinin (PHA)-stimulated normal human lymphocytes cultured for varying periods in folate-free medium and media supplemented with various concentrations of folic acid. The results indicate that when the intracellular folate content falls below 400-600 pg/10(6) cells, lymphocytes exhibit increased 3H-TdR incorporation into DNA, raised dU-suppressed values, an increase in cell volume and abnormal DNA synthesis. This critical concentration of folate is just present in resting lymphocytes, but falls on stimulation by PHA, and the effects of folate deficiency become increasingly evident beyond a culture period of 24 h unless the folic acid concentration in the medium is at least 0.32 microgram/ml. Thus human lymphocytes cultured in folate-free medium provide a model for folate-deficient DNA synthesis, but their usefulness for the performance of dU suppression tests in the diagnosis of clinical folate deficiency is likely to be limited.
Cells, Cultured↗