Antitumor Activity of alpha-Fetoprotein Conjugate with Doxorubicin in vitro and in vivo

N. B. Feldman, S. M. Kiselev, N. V. Gukasova, G. A. Posypanova, S. V. Lutsenko, and S. E. Severin^*

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

^* To whom correspondence should be addressed.

Received November 16, 1999

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alpha-Fetoprotein (AFP) was conjugated with doxorubicin (DR) using glutaraldehyde as a cross-linking agent. The protein/DR molar ratio in the conjugate is 1 : 2. Cytotoxic activities (CTA) of the AFP-DR conjugate and of the free DR were compared using human mammary gland carcinoma cells, both DR-sensitive (MCF-7^Wt) and DR-resistant (MCF-7^AdrR). The CTA of the AFP-DR conjugate was fivefold higher than the CTA of the free DR for sensitive cells of the MCF-7^Wt line and sevenfold higher for resistant cells of the MCF-7^AdrR line. The CTA of the AFP-DR conjugate was also studied in vitro using the proliferating endothelium taken for a model of endothelial cell lining of blood vessels that supply the tumor. The AFP-DR conjugate was shown to have a high CTA for the endothelial cells (IC₅₀ = 2.5 nM); thus, the conjugate is suggested to manifest an anti-angiogenic effect in vivo. The antitumor activity of the AFP-DR conjugate was studied using mice with inoculated melanoma B16 tumors. The treatment of animals significantly inhibited the tumor growth (>97%) and increased by 60% the mean life span of the animals compared to the control. The high antitumor efficiency of the AFP-DR conjugate and the possibility to significantly decrease the tumor cell resistance to DR make this conjugate a promising chemotherapeutic agent.

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KEY WORDS: alpha-fetoprotein, doxorubicin, cytotoxic activity, multiple drug resistance, proliferating endothelium, antitumor activity

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