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Molecular and Cellular Interactions between Intoplicine, DNA, and Topoisomerase II Studied by Surface-enhanced Raman Scattering Spectroscopy

Laboratoire de Spectroscopie Biomoléculaire, UFR de Pharmacie, 51096 Reims Cedex, France [H. M., I. N., M. M.]; Rhône-Poulenc Rorer, S. A., Département de Biologie, 94403 Vitry sur Seine, France [J-F. R., F. L.]; and Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, 117871 Moscow, Russia [I. N.]

The surface-enhanced Raman scattering spectra of the new antitumoral agent, intoplicine (RP 60475, NSC 645008), and those of its complexes with DNA and topoisomerase II in vitro and in K562 cancer cells were obtained.

Intoplicine was found to unwind DNA and to inhibit purified calf thymus topoisomerase II via a stabilization of the ternary cleavable complex.

The intensity of the surface-enhanced Raman scattering spectrum of intoplicine was not modified by the addition of plasmid pBR322 or calf thymus DNA. In the complex of this antitumor agent with topoisomerase II, the signal of intoplicine was completely abolished, indicating that at least some portion of intoplicine binds to an internal part of the enzyme. During the formation of the ternary complex, intoplicine was released from the interior of the protein and formed hydrogen bonds via its hydroxyl and/or amino groups.

Similar modifications of the intoplicine spectra were found by micro-surface-enhanced Raman scattering spectroscopy of the compound in the nucleus of treated K562 cells. In contrast, intopolicine was found to be in a free form in the cytoplasm.

¹ To whom requests for reprints should be addressed.

Received 3/22/93. Accepted 8/ 3/93.

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