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Uptake of Adriamycin by Rat and Mouse Mast Cells and Correlation with Histamine Release¹

Institute of Pharmacology, School of Medicine [G. D., F. B. K., L. C., L. B.], and Institute of Pharmacology and Pharmacognosy, School of Pharmacy [A. F., V. S.], University of Trieste, Via Valerio No. 32, Trieste I-34100, Italy

It has been shown recently that anthracyclines induce an important, noncytotoxic histamine release from rat and mouse peritoneal mast cells. In the present study we evaluate if histamine release is related to Adriamycin uptake; in addition the uptake of this antineoplastic drug is studied in other normal or tumor cells.

In rat and mouse peritoneal mast cells, Adriamycin-induced histamine release is quantitatively related to its intracellular concentrations. Significant differences in Adriamycin uptake are observed among mast cells and other cells. In mast cells, both the uptake of the antineoplastic drug and histamine release are greatly limited by the antiallergic drug sodium cromoglycate; on the contrary, in other normal or neoplastic cells, sodium cromoglycate only slightly reduces Adriamycin intracellular concentrations. When tested on KB cells in culture, sodium cromoglycate does not interfere with Adriamycin cytotoxicity. In mast cells, Adriamycin uptake is temperature dependent, with an optimum at 37°C, and slower than histamine release; histamine release was in fact completed in 30 s, whereas the uptake reached its maximum in 30 min. The influx is pH dependent, with a maximum at pH 6.8, and is blocked by the metabolic inhibitor antimycin A and omission of glucose. It is also possible to limit Adriamycin uptake and histamine release with the calmodulin inhibitors chlorpromazine and trifluoperazine and with the calcium antagonist nicardipine. Adriamycin efflux from mast cells is extremely rapid, temperature dependent (very slow at 0°C), but pH independent, and not modified by metabolic inhibitors.

These findings suggest that Adriamycin accumulation in mast cells involves an active transport system which can be inhibited by several agents, among which are sodium cromoglycate, and calmodulin and calcium antagonists.

¹ Supported by Grants from the Ministero della Pubblica Istruzione and C. N. R., Progetto Finalizzato Oncologia, Contract 87.01171.44.

² To whom requests for reprints should be addressed.

Received 7/29/88. Revised 12/ 9/88. Accepted 12/14/88.

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