THE DEVELOPMENT OP A [AT-211]-ASTATINATED ENDORADIOTHERAPEUTIC DRUG .2. THERAPEUTIC RESULTS FOR TRANSPLANTED ADENOCARCINOMA OF THE RECTUM IN MICE AND ASSOCIATED STUDIES

Purpose: 6-[At-211]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an on co-APase isoenzyme expressed by certain epithelial and germ cell tumor s. The therapeutic efficacy and acute toxicity of its endogenous alpha -particle emissions have been studied in a murine tumor model. Methods and Materials: At-211 was produced by the Bi-207(alpha,2n)(211) At cy clotron-based nuclear reaction. High specific activity 6-[At-211]-asta to-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isot opic exchange. The therapeutic potential of 6-[At-211]-astato-MNDP and At-211(-) was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity. Results: Significant t herapeutic effects due to targeted cr-particle emissions have been con firmed for the activity dose range, 10-750 kBq 6-[At-211]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of appro ximately 45-65% were achieved following administration of 55-300 kBq 6 -[At-211]-astato-MNDP. Estimated tumor absorbed radiation doses were n ot inconsistent with clinical response. Irreversible hematoxicity or s tigmata of acute radiation damage in other critical normal tissues wer e not encountered. Nonspecifically internalized At-211(-) exerted no t herapeutic effect. Conclusion: Therapeutic results for 6-[At-211]-asta to-MNDP have confirmed the profound in vivo cytotoxicity of its target ed alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[A t-211]-astato-MNDP endoradiotherapy is discussed, and its putative rol e in the possible individualized management of certain human tumors ha s been proposed.