The development of a [211At]-astatinated endoradiotherapeutic drug: Part II. Therapeutic results for transplanted adenocarcinoma of the rectum in mice and associated studies.
OBJECTIVE
6-[211At]-astato-MNDP is of a class of a high linear energy transfer endoradiotherapeutic drug, which selectively targets to an onco-APase isoenzyme expressed by certain epithelial and germ cell tumors. The therapeutic efficacy and acute toxicity of its endogenous alpha-particle emissions have been studied in a murine tumor model.


METHODS
211At was produced by the 207Bi(alpha,2n)211 At cyclotron-based nuclear reaction. High specific activity 6-[211At]-astato-MNDP was rapidly synthesized by in vacuo thermal heterogeneous isotopic exchange. The therapeutic potential of 6-[211At]-astato-MNDP and 211At- was determined in mice bearing a transplanted CMT-93 rectal carcinoma which exhibited onco-APase activity.


RESULTS
Significant therapeutic effects due to targeted alpha-particle emissions have been confirmed for the activity dose range, 10-750 kBq 6-[211At]-astato-MNDP. A therapeutic window has been identified, whereby cure rates of approximately 45-65% were achieved following administration of 55-300 kBq 6-[211At]-astato-MNDP. Estimated tumor absorbed radiation doses were not inconsistent with clinical response. Irreversible hematoxicity or stigmata of acute radiation damage in other critical normal tissues were not encountered. Nonspecifically internalized 211At- exerted no therapeutic effect.


CONCLUSIONS
Therapeutic results for 6-[211At]-astato-MNDP have confirmed the profound in vivo cytotoxicity of its targeted alpha-radiations in the CMT-93 tumor. Acute normal tissue toxicity was acceptable. A rationale for optimal fractionation of targeted 6-[211At]-astato-MNDP endoradiotherapy is discussed, and its putative role in the possible individualized management of certain human tumors has been proposed.
Brown
I
I
Research Laboratories, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, UK.
Mitchell
J S
JS
D000230:Adenocarcinoma / Q000532:radiotherapy*; D000818:Animals; D001246:Astatine / Q000008:administration & dosage* / Q000627:therapeutic use*; D001918:Brachytherapy; D004735:Energy Transfer; D007958:Leukocyte Count / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental; D012004:Rectal Neoplasms / Q000532:radiotherapy*; D014812:Vitamin K / Q000008:administration & dosage / Q000031:analogs & derivatives*; D024483:Vitamin K 3 / Q000031:analogs & derivatives*
D014812:Vitamin K; D024483:Vitamin K 3; C033669:astato-2-methyl-1,4-naphthoquinol diphosphate; D001246:Astatine