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Sensitization of Multidrug-resistant Mouse Ascites HD33 and Chinese Hamster Ovary CH^RC5S3 Cells by a Photoreactive Vinblastine Derivative, NAPAVIN¹

Project Molecular Biology of Mitosis [G.N., H.P.], Institute of Cell and Tumor Biology [C.G.], and Project Cytometry [M.S.], German Cancer Research Center, D-6900 Heidelberg, Federal Republic of Germany

We have synthesized a new photoreactive vinblastine derivative, 3-[[[2-amino(4-azido-2-nitrophenyl)ethyl]amino]carbonyl]-O⁴-deacetyl-3-de-(methoxycarbonyl)-vincaleukoblastine (NAPAVIN), which absorbs light at around 450 nm. We report here its effects in vitro on multidrug-resistant mouse HD33 Ehrlich-Lettré ascites cells, on Chinese hamster ovary CH^RC5S3 cells, on the corresponding drug-sensitive cells, on chemosensitive rat TMA1 mammary carcinoma, and on human SW48 colon carcinoma cells. Cells were incubated with the drug prior to activation by laser light at 457 nm. In Vinca alkaloid-sensitive cells, the short-term effects (30 to 72 h after treatment) of NAPAVIN with and without irradiation on cell proliferation are comparable to those of vinblastine. In drug-resistant cells, NAPAVIN without irradiation reduces the 50% inhibitory concentration 2- to 9-fold, compared with vinblastine. Upon irradiation with an argon laser at 457 nm, the concentration causing 50% inhibition of cell proliferation is further decreased to a total of 9- to 33-fold. Long-term effects (up to 6 wk after treatment) are seen in both sensitive and resistant cells. A single dose of the photoactivated drug causes a 6- to 9-fold larger delay (5 wk) in proliferation, compared with an equal dose of vinblastine.

¹ This work was supported by the Wilhelm and Maria Meyenburg Foundation.

² To whom requests for reprints should be addressed, at Institut für Zell-und Tumorbiologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-6900 Heidelberg, Federal Republic of Germany.

Received 6/16/89. Revised 9/14/89. Accepted 10/10/89.