Mutagenic Drugs Research Articles

Characterization of ouabain-resistant mutants of the preadipocyte Ob17 clonal line Adipose conversion in vitro and in vivo

After exposure to a mutagenic drug (ethylmethanesulfonate), mutant clones of Ob17 preadipose cells resistant to the cytotoxic action of ouabain have been isolated. Their ability to grow in serum-supplemented medium containing ⩾3 mM ouabain is consistent with the decreased ouabain sensitivity of K + transport observed in one of these clones (Ob17-OR11). Ouabain-resistant mutants retain their ability to convert into adipose-like cells in vitro with a frequency similar to that of original Ob17 cells. Long-term maintenance of Ob17-OR11 cells in ouabain-enriched medium leads to a higher frequency of adipose conversion, which is linked to a rather specific and limited growth-promoting effect of the drug. Undifferentiated Ob17-OR11 cells, when injected subcutaneously into athymic mouse, give rise in vivo to a fat pad containing ouabain-resistant mature adipocytes. Therefore, Ob17-OR11 clone should be a useful tool to distinguish in vivo between intrinsic and extrinsic factors involved in the differentiation of adipose precursor cells.

Mutagenicity of urine from nurses handling cytostatic drugs, influence of smoking.

Mutagenicity towards Salmonella typhimurium TA 100 of urine from smoking nurses, who were occupationally involved in the treatment of patients with cytostatic drugs, was significantly increased in comparison with that of smoking control subjects. Mutagenicity towards Salmonella typhimurium TA 100 was not increased in exposed non-smokers when compared to control non-smokers. In smoking subjects urinary mutagenicity appeared increased towards Salmonella typhimurium TA 1538 in the presence of S-9 mix. Rats pretreated with Aroclor 1254 showed higher mutagenicity in their urine than untreated rats after cyclophosphamide administration. Therefore, the synergistic effect of smoking might be due in part to induction of enzymes involved in the mutagenic activation of cytostatic drugs. Further, the animal experiments showed that cyclophosphamide (the most frequently used mutagenic cytostatic drug) can be absorbed after oral or percutaneous administration. Therefore, it is not excluded that differences in working hygiene between smokers and non-smokers also play a role.

Analysis of the physiological effects of the antibiotic streptozotocin on Escherichia coli K 12 and other sensitive bacteria

The antibiotic streptozotocin under a variety of growth conditions rapidly and irreversibly inactivates the capacity to divide or to form colonies of a series of sensitive bacteria, containing the phosphoenolpyruvate-dependent sugar-phosphotransferase system. Cells can be sensitized towards the drug by pregrowth in N-acetyl-glucosamine and can be protected by adding this amino-glucoside to the medium. Starvation for energy, especially for phosphoenolpyruvate, or prevention of the induction of a transport system involved in streptozotocin uptake will protect the cells, while a block in protein synthesis does not. The killed cells neither lyse, nor are they transformed into spheroplasts. At first, the capacity of such "dead" cells to respire, to swim actively or to keep the cytoplasmic membrane impermeable for small molecules remains intact. Their capacity for over-all RNA and protein synthesis, and for carbohydrate and amino acid uptake by facilitated diffusion or active transport is not affected. However, they loose rapidly their ability to take up carbohydrates by the phosphoenolpyruvate dependent process of group translocation or to synthesize inducible enzymes, e.g. the enzyme beta-galactosidase. These inhibitory effects apparently are caused by the accumulation of phosphorylated, toxic derivatives of the antibiotic and eventually lead to a pronounced bacteriostasis. Killing of the cells seems to be caused by a direct effect of the strongly mutagenic drug on replicating DNA.

Mutagenic potency and drug structure in some experimental anti-cancer drugs

Mutagenic potency and drug structure in some experimental anti-cancer drugs

Autoimmune Thrombocytopenic Purpura

Abstract Adult autoimmune throbocytopenic purpura (ATP) is a platelet disorder that develops in certain individuals with a genetic as well as sex (female) predisposition following an environment event (?viral). This results in the production of an IgG antiplatelet antibody capable of reacting with the host's platelets, as well as crossing the placenta. This leads to the rapid clearance and destruction of opsonized platelets by the reticuloendothelial system, particularly the spleen, by greater than tenfold the normal rate. Bound platelet IgG correlates with disease severity, whereas serum antiplatelet IgG does not. It has not been rigorously established whether bound platelet IgG is directed against a platelet antigen or represents an immune complex bound to the platelet Fc receptor. Nevertheless, several lines of evidence suggest that antiplatelet IgG binds directly to a platelet antigen(s). Megakaryocyte number, volume, and mass are increased commensurate with increased platelet turnover. Platelets of increased size, megathrombocytes, are noted on peripheral smear or via platelet volume distribution analysis. Megathrombocyte number is proporationate to megakarocyte number and to platelet turnover. Megathrombocyte diameter is inversely proportional to platelet survival. Antiplatelet antibody is also associated with qualitative platelet functional defects, which are indistinguishable from those noted with thrombopathia (i.e., apparent platelet release defect). Antibody-induced functional defects are probably more common than quantitative thrombocytopenic defects and may represent a significant portion of those women with the “easy bruising” syndrome and normal platelet count. Adults who develop ATP generally develop the chronic variety, which remains permanently with the patient. Treatment should be directed towards maintaining the patient free of purpura, not restoring the platelet count to normal. This can generally be accomplished with a platelet count of < 40,000/cu mm with patients having this disorder. Approximately 50% of patients respond to steroids by a significant elevation of platelet count and improvement of purpura. However, cessation of therapy results in eventual relapse if the disease is of the chronic variety. Splenectomy is successful in approximately 65–75% of patients, resulting in a restoration of the platelet count to normal or safe levels by removing a major source of platelet destruction as well as antibody production; platelet survival improves. At least 50% of patients “in remission” following steroids or splenectomy generally have a compensated thrombocytolytic state in which increased platelet production keeps up with increased platelet destruction. Antiplatelet IgG can often be found in the serum of these patients. Patients refractory to steroids and/or splenectomy present with a serious therapeutic problem. Immunosuppressive therapy is effective in approximately one-third of refractory patients, but often relapses occur, requiring maintenance therapy with potentially mutagenic drugs...

Autoimmune thrombocytopenic purpura

Adult autoimmune throbocytopenic purpura (ATP) is a platelet disorder that develops in certain individuals with a genetic as well as sex (female) predisposition following an environment event (?viral). This results in the production of an IgG antiplatelet antibody capable of reacting with the host's platelets, as well as crossing the placenta. This leads to the rapid clearance and destruction of opsonized platelets by the reticuloendothelial system, particularly the spleen, by greater than tenfold the normal rate. Bound platelet IgG correlates with disease severity, whereas serum antiplatelet IgG does not. It has not been rigorously established whether bound platelet IgG is directed against a platelet antigen or represents an immune complex bound to the platelet Fc receptor. Nevertheless, several lines of evidence suggest that antiplatelet IgG binds directly to a platelet antigen(s). Megakaryocyte number, volume, and mass are increased commensurate with increased platelet turnover. Platelets of increased size, megathrombocytes, are noted on peripheral smear or via platelet volume distribution analysis. Megathrombocyte number is proporationate to megakarocyte number and to platelet turnover. Megathrombocyte diameter is inversely proportional to platelet survival. Antiplatelet antibody is also associated with qualitative platelet functional defects, which are indistinguishable from those noted with thrombopathia (i.e., apparent platelet release defect). Antibody-induced functional defects are probably more common than quantitative thrombocytopenic defects and may represent a significant portion of those women with the "easy bruising" syndrome and normal platelet count. Adults who develop ATP generally develop the chronic variety, which remains permanently with the patient. Treatment should be directed towards maintaining the patient free of purpura, not restoring the platelet count to normal. This can generally be accomplished with a platelet count of > 40,000/cu mm with patients having this disorder. Approximately 50% of patients respond to steroids by a significant elevation of platelet count and improvement of purpura. However, cessation of therapy results in eventual relapse if the disease is of the chronic variety. Splenectomy is successful in approximately 65-75% of patients, resulting in a restoration of the platelet count to normal or safe levels by removing a major source of platelet destruction as well as antibody production; platelet survival improves. At least 50% of patients "in remission" following steroids or splenectomy generally have a compensated thrombocytolytic state in which increased platelet production keeps up with increased platelet destruction. Antiplatelet IgG can often be found in the serum of these patients. Patients refractory to steroids and/or splenectomy present with a serious therapeutic problem. Immunosuppressive therapy is effective in approximately one-third of refractory patients, but often relapses occur, requiring maintenance therapy with potentially mutagenic drugs...

Comparative data with different test systems using micro-organisms and mammalian cells on references and environmental mutagens

One of the interests of ICPEMC is to identify situations in which the possible induction of inherited defects in man by mutagen exposure could actually be studied. The large-scale use of mutagenic drugs in field programmes against schistosomiasis, mainly during the 1970's, was considered a possible case. An ICPEMC task group approached the problem by (1) updating the genetic toxicology data base for antischistosomal drugs, and (2) reviewing possible study areas. Expertise was combined from genetic toxicology, mutation epidemiology and tropical medicine.It was considered that: (a) if any, hycanthone would be the most appropriate candidate drug for study; (b) it would be virtually impossible to meet the basic requirements of an appropriate mutation epidemiology study, in endemic countries; (c) as more defined genetic endpoints would be selected (e.g. sentinel phenotypes) the required large sample sizes would seem prohibitive, since documentation on past programmes is limited and local demography would render the reliable tracking of substantial numbers of offspring of treated persons an almost impossible task; (d) in most endemic countries proper diagnosis and registration of inherited defects is largely lacking; (e) the problems encountered in demonstrating inherited effects in humans after heavy or chronic exposure to established animal mutagens such as ionizing radiation and cancer chemotherapy, in combination with the ambiguous nature of the animal germ cell data with hycanthone, do not particularly warrant large expectations; (f) since non-mutagenic antischistosomal drugs are now in use, the problem is academic and of low priority in the endemic countries whose medical and research resources are often limited. Thus, studying offspring of hycanthone-treated people to demonstrate the mutagenic potential of the drug in man is not a viable enterprise. (See, however, note added in proof, p. 75.)

The mutagenic activity of anti-cancer drugs and the urine of rats given these drugs

Twenty-one anti-cancer drugs have been tested for their ability to cause mutations in Salmonella typhimurium test strains in the Salmonella/microsome mutagenicity test. Nine of the 21 anticancer drugs showed this ability: cyclophosphmide, nitromin, thio-tepa, busulfan, 6-mercaptopurine, neocarzinostatin, daunomycin, adriamycin and estramustine phosphate. Seven of these 9 mutagenic drugs were injected continuously into the jugular veins of rats. Urine was collected through a cystostomy tube and tested for mutagenicity. The urine from rats treated with 6 of these 7 drugs was mutagenic. These were cyclophosphamide, nitromin, thio-tepa, neocarzinostatin, adriamycin and daunomycin.

Multiple Myeloma on Polycythemia Vera Following Radioactive Phosphorus Therapy

A 74-year-old white man with established polycythemia vera was treated with radioactive phosphorus after phlebotomies alone failed to control his disease. About 2 3/4 years later he died of multiple myeloma. The mutagenic effect of radioactive phosphorus may have caused or possibly accelerated preexisting myeloma. Basic nonmalignant disease deserves careful consideration before radiation or radiomimetic agents are used. One might consider a probably less mutagenic drug such as hydroxyurea in patients with polycythemia vera when phlebotomy alone does not give good control of red cell mass and thrombocytosis.

INTERACTION BETWEEN PROFLAVINE AND GUANOSINE 5‘‐PHOSPHATE: IMPORTANCE OF PHOTOEXCITATION

Abstract— The stoichiometry of the complex formed between the mutagenic drug proflavine and the nucleotide guanosine 5'‐phosphate has been demonstrated to be 1:1. Its association constant at room temperature is found to increase from 310 M‐1 when proflavine is in its ground electronic state, to 1550 M‐1, when proflavine is in its first excited singlet state. Thus, light absorbed by the drug alters its reactivity which, in turn, results in an appreciable increase in its ability to bind to the nucleotide. The enthalpy and the entropy of the ground state proflavine‐guanosine 5'‐phosphate complex formation are ‐12.6 kJ/mol (‐3 kcal/mol) and ‐6.7 J/mol/deg (‐1.6 cal/mol/deg), respectively. The implications of these findings concerning the proflavine‐DNA interaction as well as the possible importance of electronic excitaton in acridine mutagenesis are discussed. An appraisal of the methodology for analyzing fluorescence quenching data is also given.

ON THE NATURE OF INTERACTION BETWEEN PROFLAVINE and DNA

Abstract— The fluorescence decay of the mutagenic drug proflavine (PF) bound to DNA at a phosphate‐to‐drug ratio of 420 is found to be a non‐exponential function of time. The deviation from exponentiality is shown to increase with increasing GC content of DNA. Thus, heterogeneity in the high affinity binding sites is clearly demonstrated. The nucleotides guanosine‐5‘‐monophosphate (GMP) and cyti‐dine‐5’‐monophosphate (CMP) are shown to form complexes with PF in 10‐3M sodium cacodylate buffer at pH 6.6. In addition, GMP quenches substantially the fluorescence of PF while CMP enhances it slightly. The fluorescence decay curves for 5 × I0‐6M PF in the presence of GMP concentrations greater than 10‐2M exhibit a deviation from exponentiality which parallels that exhibited by the fluorescence decay curves for PF bound to DNA of increasing GC content. It is inferred that (a) guanine is responsible for the quenching of the fluorescence of PF on binding to DNA; and (b) the forces involved in the interaction between PF and DNA are specific in nature. The implications of these findings concerning the mutagenic properties of acridine derivatives are discussed. Nanosecond depolarization studies reveal a quite fast depolarization of the fluorescence of bound PF; for the PF‐Cl. perfringens DNA complex the rotational correlation time is about 26 ns. Time‐resolved emission spectroscopy in the nanosecond scale demonstrates that, despite the change in the orientation of the drug, the electronic structure of the PF‐DNA complex is not substantially altered during the lifetime of the excited singlet electronic state of the drug.

Autoimmune thrombocytopenic purpura.

Adult autoimmune throbocytopenic purpura (ATP) is a platelet disorder that develops certain individuals with a genetic as well as sex (female) predisposition following an environment event (?viral). This results the production of an IgG antiplatelet antibody capable of reacting with the host's platelets, as well as crossing the placenta. This leads to the rapid clearance and destruction of opsonized platelets by the reticuloendothelial system, particularly the spleen, by greater than tenfold the normal rate. Bound platelet IgG correlates with disease severity, whereas serum antiplatelet IgG does not. It has not been rigorously established whether bound platelet IgG is directed against a platelet antigen or represents an immune complex bound to the platelet Fc receptor. Nevertheless, several lines of evidence suggest that antiplatelet IgG binds directly to a platelet antigen(s). Megakaryocyte number, volume, and mass are increased commensurate with increased platelet turnover. Platelets of increased size, megathrombocytes, are noted on peripheral smear or via platelet volume distribution analysis. Megathrombocyte number is proporationate to megakarocyte number and to platelet turnover. Megathrombocyte diameter is inversely proportional to platelet survival. Antiplatelet antibody is also associated with qualitative platelet functional defects, which are indistinguishable from those noted with thrombopathia (i.e., apparent platelet release defect). Antibody-induced functional defects are probably more common than quantitative thrombocytopenic defects and may represent a significant portion of those women with the easy bruising syndrome and normal platelet count. Adults who develop ATP generally develop the chronic variety, which remains permanently with the patient. Treatment should be directed towards maintaining the patient free of purpura, not restoring the platelet count to normal. This can generally be accomplished with a platelet count of > 40,000/cu mm with patients having this disorder. Approximately 50% of patients respond to steroids by a significant elevation of platelet count and improvement of purpura. However, cessation of therapy results eventual relapse if the disease is of the chronic variety. Splenectomy is successful approximately 65-75% of patients, resulting a restoration of the platelet count to normal or safe levels by removing a major source of platelet destruction as well as antibody production; platelet survival improves. At least 50% of patients in remission following steroids or splenectomy generally have a compensated thrombocytolytic state which increased platelet production keeps up with increased platelet destruction. Antiplatelet IgG can often be found the serum of these patients. Patients refractory to steroids and/or splenectomy present with a serious therapeutic problem. Immunosuppressive therapy is effective approximately one-third of refractory patients, but often relapses occur, requiring maintenance therapy with potentially mutagenic drugs...

Drosophila-tests in pharmacology.

IN a communication under this heading, Luning1 has suggested a routine procedure by which potentially mutagenic drugs can be screened in tests on Drosophila. He uses developmental delay as the type of somatic damage that is likely to be correlated with whatever genetical damage has occurred. I wish to point out that in the only instance in which, to my knowledge, the effects of the same mutagen on developmental delay and mutation frequency were investigated, the correlation between them was clearly and strikingly negative. When larvae are raised on food to which formaldehyde at a low concentration has been added, high mutation frequencies are obtained so long as development proceeds at the normal speed. Any condition that delays development of the treated larvae—be this shortage of food, poor quality of food, supplementary harmful treatments, or even a more than optimal concentration of formaldehyde—concomitantly decreases mutation frequency2. For this particular mutagen, therefore, developmental delay would be a highly misleading guide to mutagenicity. It is, of course, possible that formaldehyde is exceptional in this respect, and that Luning's test might be more reliable for other chemicals. Before this can be assumed, however, it will be necessary to establish experimentally for at least one member of the group of chemicals to be screened that its mutagenic action is positively correlated with its delaying action on development.