Differences In Drug Sensitivity Research Articles

Naturally occurring differential drug sensitivities of cultured plant protoplasts

The growth of protoplasts isolated from petunia and tobacco leaves has been assessed in the presence of a range of concentrations of various amino acid analogues, growth substances and other drugs. Some of the compounds showed no differential effect on the growth of the protoplasts. Several of the drugs, however, showed a pronounced differential effect preventing the growth of tobacco protoplasts while at the same concentration allowing the growth of petunia protoplasts, and with certain other drugs the converse situation prevailed. It is suggested that such naturally occurring differential drug sensitivities might provide a basis for the complementation selection of somatic hybrids arising from the culture of fused protoplasts.

The growth of human tumours in immunosuppressed mice and their response to chemotherapy.

One hundred and sixteen human tumours were transplanted to thymectomized, irradiated, antilymphocyte serum-treated mice. In 12 cases the recipient mice died rapidly, presumably from infection. With the remaining 104 tumours, three-quarters grew to a varying extent, retaining the characteristic histological features of the primary tumours. Implant nodules varied widely in composition, from solid tumour and stroma to dense fibrous tissue without recognizable tumour cells. There was no relation between degree of malignancy and ability to grow, and also some benign tumours grew.In 44 cases, mice were treated with the drug or drugs most likely to be used in the patients and the effects on the implants were assessed histologically. Two tumours were largely destroyed and one showed marked metaphase arrest. Three other tumours showed lesser changes that were attributable to the drug but were of equivocal significance.There appeared to be differences in drug sensitivity between structurally different clones of the same tumour, and some tumours treated with two alkylating agents were damaged by one and not the other, suggesting that this model may have substantial discriminatory power. Assays such as this should not be used to guide treatment of the patient without prior validation. The practical and ethical difficulties of validation by clinical trial may be insurmountable, and an alternative approach to validation is proposed which does not raise these difficulties.

The characterisation of [ 3H]GABA uptake into the satellite glial cells of rat sensory ganglia

The accumulation of [ 3H]GABA in rat sensory ganglia in vitro is exclusively localised within satellite glial cells. Using a GABA concentration of 1 × 10 −7 M, the uptake continued linearly for 4 h in the presence of 10 μM amino-oxyacetic acid (AOAA) attaining a tissue/medium ratio of 100:1; in the absence of AOAA the uptake started to saturate after 2 h, the tissue/medium ratio being 25:1. The uptake appeared to be mediated by a kinetically saturable process with an apparent K m of 10 μM (high affinity) and was extremely dependent on the presence of external sodium ions. Drug inhibition studies indicated that the high affinity uptake was not inhibited by the GABA receptor antagonists bicuculline and picrotoxin or by the amino acids glutamate, glycine or glutamine. Detailed comparison of the inhibition properties of certain GABA analogues and other pharmacological agents revealed direct differences between cortical slices and sensory ganglia. l-2,4-Diaminobutyric acid was 20 times more potent an inhibitor of uptake in cortical slices than in sensory ganglia; conversely β-alanine was 200 times more potent an inhibitor of sensory ganglion uptake. Chlorpromazine and p-chloromercuriphenyl sulphonate were far less potent inhibitors of the ganglia than the cortical slices. In conclusion the uptake process of glial cells in sensory ganglia shows certain distinct differences from that of cortical neurones. The rate of GABA uptake in the ganglia is much slower than in the cortex. This may result from the low V max value in the ganglia indicating a sparsity of uptake sites. The ganglion uptake is greatly enhanced in the presence of AOAA implying a rapid catabolism of GABA taken into glial cells by the enzyme GABA: glutamate transaminase. The differences in drug sensitivity indicate that the two active transport systems exhibit different binding sites.

Human brain and platelet cyclic adenosine 3′,5′-monophosphate phosphodiesterases: Different response to drugs

Cyclic AMP phosphodiesterase from human platelets is strongly inhibited by dipyridamole, an antagonizer of platelet aggregation, and only slightly by psychotropic drugs. The reverse situation is observed with the brain enzyme. Distinct electrophoretic patterns of phosphodiesterase are found in these tissues. The existence of different isoenzymes may explain differential drug sensitivity.

LEUKAEMIC SUBCLONES IN CHRONIC MYELOGENOUS LEUKAEMIA

Abstract. Serial karyotype studies have been done during cytostatic treatment in a patient with CML in blastic crisis. A course of cytosine arabinoside and thioguanine resulted in a dramatic decrease in the frequency of a 54‐chromosome clone and simultaneous increases of a 46, XY and a 50‐chromosome clone. At the same time the cytological composition of the bone marrow changed towards normal and some temporary clinical improvement took place. Comparison of data on karyotypes and cytology suggest that the highly abnormal karyotypes represented myeloblasts and promyelocytes, whereas early red cell precursors were 46, XY cells. In the discussion the following suggestions are made: (A) Heterogeneity of a leukaemic cell population, as evidenced by differences in karyotypes, may be associated with differences in drug sensitivity. This represents a rationale for multiple drug therapy. (B) Differentiation of leukaemic cells may not be compatible with highly abnormal karyotypes; in turn, lack of differentiation may result in a growth advantage of cells with severe karyotype abnormalities, which would explain the typical evolution of CML from a condition characterized by a single karyotype abnormality (the Ph1‐chromosome) and successful differentiation to a state with multiple karyotype abnormalities and lack of cell differentiation, ending in blastic crisis. (C) It might be possible to postpone the development of blastic crisis if treatment was directed against the developing abnormal clones during the chronic phase of CML. It is proposed to study the use of intermittent intensive chemotherapy in the chronic phase of CML. In a preliminary observation of incipient malignant karyotype evolution in a patient with CML, the secondary karyotype abnormalities almost disappeared after a course of cytosine arabinoside and thioguanine.

DNA repair after mustard gas alkylation by sensitive and resistant Yoshida sarcoma cells in vitro

The ability of the alkylating agent-resistant sub-line of the Yoshida sarcoma to recover from DNA alkylation by mustard gas has been compared with the original drug-sensitive tumour line. In cell culture the level of alkylation of DNA, the rate of excision of alkylated moieties and the ability to carry out non-semi-conservative DNA synthesis following mustard gas treatment were compared. No difference between the cell lines in these respects has been found which might account for the observed 20-fold difference in drug sensitivity in terms of DNA repair mechanisms.

Genetics of Entamoeba histolytica: Differences in Drug Sensitivity between Laredo and other Strains of Entamoeba histolytica*

SYNOPSIS. The “Laredo strain” of Entamoeba histolytica has been reported to have different temperature requirements for growth than the usually known strains of the species, although morphological and antigenic tests have thus far indicated no significant recognizable differences. Further genetic studies show the Laredo strain to exhibit at least four characteristics different from the usual. Also, a freshly isolated strain (BA) was shown to have the same characteristics as those previously reported for some well‐known strains.

The Action of Various Agents upon the Rabbit Embryo

ABSTRACT A study was made of the action upon the rabbit embryo of various agents administered to pregnant animals in doses which did not seriously upset maternal health. The pre-implantation blastocyst, examined as a flat mount, was the principal object of study, but observations were also made on ovulation, fertilization, cleavage, nidation, and subsequent phases of pregnancy. To facilitate comparison between embryos from normal and treated animals 5-to 7-day-old blastocysts from untreated animals, grouped according to size, were classified into 6 developmental stages, depending upon the degree of maturity of the embryonic disc. Additional procedures which served to evaluate the condition of blastocysts and their uterine environment were: mitotic counts made in the abembryonic part of the trophoblast, chemical determinations of certain characteristic constituents of blastocyst fluid, and measurement of carbonic anhydrase activity in the endometrium. . The experimental agents comprised hormones, colchicine derivatives, several polyfunctional alkylating compounds, metabolic analogues, a sulphonamide inhibitor of carbonic anhydrase, and substances endowed with teratogenic, hepatotoxic, radiation-protective, and hypoglycaemia-inducing properties; total body exposure to X-rays was also investigated. Results obtained at various stages of pregnancy with the different treatments are described and discussed; several results relating to blastocysts are illustrated by photomicrographs. Among significant general findings emerging from the study are: the speed with which exogenous agents are transmitted to embryos even before uterine attachment; differential drug sensitivity, frequently evident in the pre-implantation blastocysts, as between the embryonic disc and trophoblast, the former usually being more susceptible; and variability in response, both individual and between litters, of the embryos to parenterally administered agents. It is suggested that the blastocyst flat mount preparation could be adapted as a conveniently rapid and simple procedure for the screening of cytostatic and other growth-modifying agents.

Sedation threshold, personality, and the theory of neurosis.

For many years it has been observed that individuals differ in their tolerance of depressant drugs. In everyday life differential susceptibility to the effects of alcohol is that most commonly observed and this fact led to McDougall's early theorizing (1929) about drug tolerance and personality. Also at this time Pavlov, in dogs, recorded differences in drug sensitivity in his various temperamental types. However, the first attempt to measure individual differences in drug tolerance was made by Shagass (1954), who proposed the concept of “sedation threshold”. This was defined in terms of the amount of sodium amytal required to bring about certain behavioural and other changes in the individual, the threshold itself lying somewhere between the state of complete wakefulness and that of complete sedation. Two methods of determining the threshold were employed by Shagass. First, the point of onset of slurred speech gave an approximate estimate of its position. Secondly, a more accurate determination was made by means of EEG changes, specifically the point at which inflexion occurs in the amplitude curve of induced fast frontal activity.

Comparative and quantitative studies of fungitoxicity against fungal spores and mycelia.

In studies on the mode of action of antifuingal agents, it may be valuable to reveal the difference in drug sensitivity between fungal spores and mycelia. Various methods employed in the evaluation of antifungal substances do not necessarily apply to the solution of this problem. For the estimation of sporostatic activity of an agent, the inhibitory effect on the course of germination of spores can be taken as a measure of (luantitative evaluation of the activity. On the other hand, the quantitation of growth inhibitory activity oni mycelia (mycostatic activity) of an agent is much more complicated. In the present experiment, mycelial fragments prepared from pellets formed in the submerged culture of a fungus were used for the quantitative evaluation of mycostatic as well as the activities of a given agent. The mycelial fragments formed individual colonies on agar media. Therefore, techniques for bacteriostatic and bactericidal tests routinely employed could be easily modified to mycostatic and mycocidal tests.

Comparative and Quantitative Studies of Fungitoxicity against Fungal Spores and Mycelia1

In studies on the mode of action of antifuingal agents, it may be valuable to reveal the difference in drug sensitivity between fungal spores and mycelia. Various methods employed in the evaluation of antifungal substances do not necessarily apply to the solution of this problem. For the estimation of "sporostatic" activity of an agent, the inhibitory effect on the course of germination of spores can be taken as a measure of (luantitative evaluation of the activity. On the other hand, the quantitation of growth inhibitory activity oni mycelia ("mycostatic" activity) of an agent is much more complicated. In the present experiment, mycelial fragments prepared from pellets formed in the submerged culture of a fungus were used for the quantitative evaluation of mycostatic as well as the "mycocidal" activities of a given agent. The mycelial fragments formed individual colonies on agar media. Therefore, techniques for bacteriostatic and bactericidal tests routinely employed could be easily modified to mycostatic and mycocidal tests.