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Reappraisal of the Association between Adriamycin and Iron¹

Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem 91010, Israel

The nature of the association between Adriamycin (ADR) and iron was reinvestigated spectroscopically. It is shown that ADR and Fe³⁺ do not necessarily form a colloidal aggregate, but rather form a true chelate, Fe³⁺ ADR₃, having a 602-nm molar extinction coefficient of 16.4 mM^-1·cm^-1. In contrast to the high nominal binding constant for ferric-ADR, ß = 10^33.4, it is shown that under actual conditions of metal hydrolysis and ADR protonation, the effective binding constant, K_eff, is strongly pH dependent and is only 10^16.2M^-3 at pH 7.4. These properties are reflected in a progressive dissociation of Fe³⁺ ADR₃ upon dilution and at decreasing pH. Maximal iron chelation by ADR is not achieved at [ADR]:[iron] ratios lower than 10:1, and at [ADR] below the 0.1 mM range. These observations necessitate a reevaluation of previous conclusions regarding the involvement of iron in ADR activity. The clinical implications are important, because at ADR concentrations obtained in vivo, and contrary to common assumptions, ADR will not bind adventitious iron to form a binary chelate. Furthermore, a preformed Fe³⁺ ADR₃ chelate will dissociate when injected. This precludes the involvement of a binary ferric-ADR chelate in the mechanism of action of ADR in vivo.

¹ This research was supported by Grant 85-00246 from the U. S.-Israel Binational Science Foundation, Jerusalem, Israel.

² To whom requests for reprints should be addressed.

Received 2/16/88. Revised 6/23/88. Accepted 7/ 5/88.

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