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In Vivo Antitumor Activity and in Vitro Cytotoxic Properties of Bis[1,2-bis(diphenylphosphino)ethane]gold(I) Chloride

Department of Chemistry, Birkbeck College, University of London, Malet Street, London, WCIE 7HX, United Kingdom [S. J. B.-P., P. J. S.], and Department of Molecular Pharmacology, Smith Kline and French Laboratories, Swedeland, Pennsylvania 19479 [C.-M. S., R. K. J., M. R. M., F. L. M., L. F. F., S.-M. M., C. K. M., S. T. C]

We have previously reported the cytotoxicity and antitumor activity of bis(diphenylphosphino)ethane (DPPE) and a variety of its transition metal complexes. During studies of the chemistry of a gold complex of this group [(AuCl)₂(DPPE)], it was observed that this complex readily underwent ring closure on reaction with DPPE to form the tetrahedral complex [Au(DPPE)₂]⁺. Various counterion forms (e.g., Cl^-) of this cation were isolated and were found to exhibit a remarkably high stability in solution. Evaluation of [Au(DPPE)₂]Cl in mice bearing i.p. P388 leukemia demonstrated that the compound produced an average of 87% increase in life span at its maximally tolerated dose (2–3 µmol/kg/day for 5 days). Activity was also seen in i.p. M5076 reticulum cell sarcoma (60% increase in life span) and s.c. mammary adenocarcinoma 16/c. Modest activity was evident in i.p. B16 melanoma and L1210 leukemia. A subline of P388 leukemia resistant to cisplatin was not cross-resistant to [Au(DPPE)₂]Cl. In addition, combination therapy of [Au(DPPE)₂]Cl and cisplatin against i.p. P388 demonstrated an advantage over single-agent therapy.

In vitro studies of [Au(DPPE)₂]Cl showed that the compound: (a) is cytotoxic to tumor cell lines; (b) is only minimally inhibited in its cytotoxic activity by the presence of serum; (c) produces DNA protein cross-links and DNA strand breaks in cells; and (d) inhibits macromolecular synthesis with a preferential inhibitory effect on protein synthesis relative to DNA and RNA synthesis. ³¹P nuclear magnetic resonance spectroscopy indicated that the compound is stable in the presence of serum proteins, thiols, or disulfides and that it reacts with Cu(II) resulting in the formation of a Cu(I)DPPE complex. The results of these in vivo and in vitro experiments suggest that the contrasting pharmacological profile of [Au(DPPE)₂]Cl with respect to other gold(I) phosphine complexes may be related to both the kinetic stability of the complex and its stability in the presence of thiols.

¹ To whom requests for reprints should be addressed, at Birkbeck College, University of London, Malet Street, London, WCIE 7HX, United Kingdom.

Received 5/23/86. Revised 7/31/86. Accepted 8/ 5/86.