Cytotoxic Action of Conjugates of alpha-Fetoprotein and Epidermal Growth Factor with Photoheme, Chlorines, and Phthalocyanines

A. A. Savitsky¹, N. V. Gukasova¹, S. G. Gumanov¹, N. B. Feldman¹, E. A. Luk'yanets², A. F. Mironov³, R. I. Yakubovskaya⁴, S. V. Lutsenko¹, and S. E. Severin^1*

¹Moscow Research Institute of Medical Ecology, Simferopolskii Bul'var 8, Moscow, 113149 Russia; fax: (7-095) 113-4818; E-mail: sergsev@aha.ru

²State Research Center, Institute of Organic Semiproducts and Dyes, Bol'shaya Sadovaya ul. 1/4, Moscow, 103787 Russia; fax: (7-095) 254-1200; E-mail: rmeluk@cityline.ru

³Lomonosov Moscow State Academy of Fine Chemical Technology, pr. Vernadskogo 86, Moscow, 117571 Russia; fax: (7-095) 434-8711; E-mail: mironov@httos.mitht.msk.ru

⁴Herzen Moscow Research Oncology Institute, 2-oi Botkinskii Proezd 3, Moscow, 125284 Russia; fax: (7-095) 954-6882; E-mail: raisa@yakubov.genebee.msu.ru

^* To whom correspondence should be addressed.

Received September 27, 1999; Revision received November 16, 1999

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Covalently bound conjugates of alpha-fetoprotein (AFP) and epidermal growth factor (EGF) with photoheme (PH), 3-desvinyl-3-formylchlorine p₆ (Chl p₆), chlorine e₆ (Chl e₆), aluminum disulfochloride phthalocyanine (PC(Al)), and cobalt octa-4,5-carboxyphthalocyanine (teraphthal, TP(Co)) were synthesized. Their molar ratios were 1:4 for AFP-cytotoxin conjugates (cf. 1:10 for AFP-TP(Co)) and 1:2 for EGF conjugates (cf. 1:1 for EGF-PC(Al)). Dark toxicity of both protein conjugates with PH, chlorines, and PC(Al) was much lower than their phototoxicity. Studies on phototoxicity demonstrated that PC(Al) conjugates with AFP and EGF and also EGF-Chl p₆ were the most effective. The cytotoxic activity (CTA) of AFP-PC(Al) and EGF-Chl p₆ was 80% and of EGF-PC(Al) 64% higher than the CTA of the free drugs. Conjugates with TP(Co) were much more toxic on their activation with ascorbic acid (AA): in the presence of AA the CTA of AFP-TP(Co) and of EGF-TP(Co) was 19 and 61.1% higher, respectively, than the CTA of the free TP(Co).

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KEY WORDS: alpha-fetoprotein, epidermal growth factor, conjugates, cytotoxic activity, phototoxicity, dark cytotoxic activity, tumor cells

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