The objective of the proposed research is to synthesize actinomycin analogues suitable for conjugation to tumor-specific proteins. Such drug-protein conjugates should possess antitumor efficacy superior to that of actinomycin alone. Malignant cells would be subjected to far higher drug concentrations than those reaching normal cells, thus minimizing side effects. Targeting studies of this kind with other antitumor agents such as daunomycin and adriamycin have been reported. In order to succeed with this approach the following aspects must be considered: (a) Selection of a suitable drug: actinomycin is appropriate because of its stability and high potency. However, there is no group on the molecule suitable for covalent linkage to a protein. The principal objective of the proposed research will be to produce modified actinomycins which possess a linking group and retain antitumor potency. (b) Selection of the carrier protein: ideally this should consist of an antibody specific towards a tumor-associated antigen or a mixture of such antibodies. (c) Selection of a spacer group: such a group, interposed between drug and carrier, will be degraded by lysosomal enzymes after the conjugate enters the tumor cell, with release of the drug. Short peptides have proven valuable in this role. (d) Methodology of conjugation: this is a critical factor which must preserve both drug activity and antibody activity. This is a collaborative project. The principal investigator will synthesize actinomycins modified at various sites in the molecule and couple them to spacer peptides. Those modifications which retain antitumor activity comparable with that of actinomycin D will then be conjugated with antitumor antibodies by Dr. Meir Wilchek at the Weizmann Institute of science, Rehovoth, Israel. This collaborator, who has experience with daunomycin and adriamycin-antibody conjugates, will test the efficacy of the actinomycin-antibody conjugates in the related animal tumor systems. A number of possibilities will be produced and compared in order to identify the most efficacious analogue for targeting studies. It is hoped that such investigations will be extended to conjugates with human tumor antibodies and that the possibility of clinical trials will be realized.
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