L. Baldini

Characterization of histamine secretion induced by anthracyclines in rat peritoneal mast cells

The histamine-releasing activity of three anthracyclines, adriamycin, daunomycin and epirubicin, has been tested on rat peritoneal mast cells. The three drugs induced a marked and dose-dependent histamine secretion, in a noncytotoxic manner. The release was not sustained by extracellular calcium but was largely dependent on intracellular stores of this cation. This function was blocked by extremes of temperature (0 and 45 degrees), was very rapid and virtually complete within 10 sec. Treatment of mast cells with theophylline or disodium cromoglycate significantly reduced the secretory response to anthracyclines. On the basis of these results it is clear that the stimulant effect of anthracyclines is a true exocytotic response and thus is very similar to that of the classic mast cell secretagogue, compound 48/80.

Adriamycin-induced histamine release from heart tissue in vitro.

Abstract It has been proven that the anthracyclines induce an important, noncytotoxic histamine release from rat peritoneal mast cells. As mast cells derived from different tissues exhibit marked heterogeneity, the effect of Adriamycin in comparison with other antineoplastic agents was tested on fragments of the right heart auricle, which contain a great number of mast cells. In this experimental model, Adriamycin induced a dose-dependent histamine release that was significantly limited by the antiexocytotic drug sodium cromoglycate. The antineoplastic agents cisplatin and 5-fluorouracil, in contrast, did not provoke any comparable histamine release. In the formulation employed in clinical settings, paclitaxel was also capable of inducing a histamine release comparable with that of Adriamycin; the exocytotic activity, however, was also evident when the tissue fragments were treated with Cremophor EL alone, without the addition of paclitaxel, whereas treatment of samples with paclitaxel dissolved in ethanol did not induce any releasing action. These data thus suggest that the secretory activity should be ascribed to the solvent Cremophor EL and not to paclitaxel. The release of histamine induced by paclitaxel in Cremophor EL/ethanol was also limited by sodium cromoglycate. These results again indicate that histamine release from mast cells derived not only from the peritoneal cavity but also from the cardiac tissue could play a role in the cardiotoxicity of anthracyclines and of paclitaxel in the clinically employed formulation.

Amelioration of 4'-Epidoxorubicin-induced cardiotoxicity by sodium cromoglycate.

Epirubicin induces an important noncytotoxic release of histamine from rat peritoneal cells in vitro. This exocytotic response is inhibited by sodium cromoglycate, similarly to that elicited by the classic mast cell secretagogue, compound 48/80. Mast cells obtained from the peritoneal cavities of rats treated with epirubicin in vivo were extensively degranulated; in contrast, samples obtained from rats pretreated with sodium cromoglycate showed normal appearing mast cells. When injected i.p., immediately before the antineoplastic agent, cromolyn significantly improved the survival time and the microscopic appearance of myocardial tissues of epirubicin-treated mice. The results indicate that histamine release could play an important role in the pathogenesis of anthracycline-induced cardiotoxicity.

Dimethyl sulfoxide inhibits histamine release induced by various chemicals

Dimethyl sulfoxide was found to inhibit histamine release induced by compound 48/80 at concentrations ranging from 0.6 to 10%. At higher concentrations (20 and 40%) the substance caused histamine release by itself. Heat inactivation at 50°C of the mast cells did not prevent this release, suggesting a lytic mechanism for this action and this was further proved by the trypan blue dye exclusion test. Dimethyl sulfoxide was also active in inhibiting histamine release induced by other polyamines such as bradykinin, polymyxin B and protamine, by concanavalin A and dextran, by ionophore A23187 and by three anthracyclines, doxorubicin, daunomycin and epirubicin. In contrast, the substance did not inhibit histamine release induced by a monoamine, chlorpromazine and by the detergent Triton X-100.

Effect of polyethylene glycol 400 on adriamycin toxicity in mice

The effect of a widely used organic solvent, polyethylene glycol 400 (PEG 400), on the toxic action of an acute or chronic treatment with adriamycin (ADR) was evaluated in mice. PEG 400 impressively decreased both acute high-dose and chronic low-dose-ADR-associated lethality. Light microscopic analysis showed a significant protection against ADR-induced cardiac morphological alterations. Such treatment did not diminish the ADR antitumor activity in L1210 leukemia and in Ehrlich ascites tumor.

Effect of ketotifen on adriamycin toxicity: Role of histamine

The effect of ketotifen, an antianaphylactic drug which acts in part similarly to sodium cromoglycate, was tested on adriamycin-induced histamine release and toxicity. The intraperitoneal injection of various concentrations of ketotifen induced an important histamine release from rat mast cells. Thirty minutes after the injection, however, no more histamine was present in the peritoneum. When i.p. administered to mice 30 min before adriamycin (15 mg/kg), ketotifen significantly ameliorated the survival time and reduced the cardiotoxicity. On the contrary, when given simultaneously, the antiallergic drug increased the toxic effect of adriamycin.

Effects of diazoacetyl-glycine amide on purine nucleotide and deoxyribonucleic acid synthesis in ehrlich ascites tumor cells

Abstract Ascites tumour cells derived from diazoacetyl-glycine amide-treated animals show a reduced incorporation of labelled thymidine, whereas the incorporation of labelled uridine and leucine is unchanged with respect to control cells. The in vivo incorporation of both thymidine-H 3 and adenine 8-C 14 into DNA of tumour cells, is also inhibited by a previous injection of diazoacetyl-glycine amide into the animals. The utilization of adenine 8-C 14 for RNA synthesis is not affected under these conditions, whereas the amount of formate-C 14 recovered in both DNA and RNA fractions is significantly reduced. These results suggest that the antitumor drug diazoacetyl-glycine amide is capable of inhibiting the purine nucleotide and DNA biosynthesis.

Adriamycin Binds to the Matrix of Secretory Granules during Mast Cell Exocytosis

The antineoplastic drug adriamycin induces exocytosis in rat peritoneal mast cells followed by a significant uptake of the drug into the secretory granules. The drug is fluorescent, allowing visualization of its accumulation and binding to mast cell granules by fluorescence microscopy. At the same time, the well known inorganic dye ruthenium red was used as a probe because of its great affinity for heparin in the mast cell secretory granules as visualized by bright field microscopy. Competition between adriamycin and ruthenium red for binding to the negatively charged matrix of granules was demonstrated. Biochemical studies were also performed to confirm microscopic observations. Adriamycin may be of interest for studying mast cell secretion; it is not only a strong fluorescent dye for mast cell granules that are in communication with the extracellular space, but it also induces mast cell exocytosis.

Effect of polyethylene glycol 400 on adriamycin induced histamine release

The activity of polyethylene glycol 400, a widely used drug solvent, was tested on the release of histamine induced by adriamycin in vitro on peritoneal rat mast cells and in vivo in a mouse model. Preincubation of mast cells with high (10 and 5%) concentrations of polyethylene glycol 400 significantly inhibited the important histamine release induced by 100 micrograms/ml of adriamycin; furthermore, polyethylene glycol 400 (3.45 g/kg; 0.345 g/ml) pretreatment almost completely abolished the peritoneal and pericardial mast cell degranulation and the cardiac toxicity caused by an intraperitoneal injection of 15 mg/kg of adriamycin. This effect of polyethylene glycol 400 on adriamycin-induced histamine release could explain the protective action exhibited in vivo on adriamycin treated animals, therefore confirming that adriamycin cardiotoxicity could be related to the release of histamine and other vasoactive substances.

Mechanism of inhibition of dna synthesis in ehrlich ascites tumour cells by diazoacetyl glycine-amide.

Abstract Treatment of Ehrlich ascites carcinoma bearing mice with DGA, the amide of diazoacetyl-glycine, leads to an inhibition of labelled thymidine incorporation into DNA of the tumour cells. This inhibition is not due to impairment of the nucleoside transport into the cell or to a modification in the activity of thymidine kinase. A possible explanation of the DGA effects resides in its partial inhibition of DNA polymerase and in its ability to alter the template activity of native DNA.