Summary of Informal Discussions on the Role of Pyrimidine Antagonists following Papers by Dr. Prusoff and Dr. Calabresi.

inquired about the evi dence for the absorption of azauridine from the intestine and made the following comments con cerning 5-iododeoxyuridine (IUDR), in view of Szybalski's demonstration of radiosensitization of human cells after their incorporation of IUDR into DNA: â€oeIncollaboration with him and Dr. Kelly Clifton of our Radiology Department we have done some studies in mice with transplanted mammary tumors with I'2@-labeled IUDR. Our studies differed from most others, who used tracer doses, in that we used chemotherapeutic doses. We found a retention of the label in the DNA of the tumors, whereas it disappeared rapidly from the DNA of the liver, spleen, and intestines. We also gave the labeled IUDR to two patients prior to surgery, and found in their tumors an incorpo ration into DNA that was roughly comparable to that found in the mouse tumors. According to Dr. Szybalski, there should be enough incorporation into the human tumor DNA to produce some radiosensitization; therefore, IUDR can get into the DNA of solid tumors in mice and in man, in spite of the rapid degradation it undergoes.†• DR. CALABRESI pointed out, concerning azauri dine (AzUR), that ordinarily it is administered in travenously, because AzUR is poorly absorbed by man, a species in which absorption of AzUR from the alimentary tract contrasts markedly with the excellent utilization seen in the mouse and the dog. With triacetyl-azauridine, however, which is very well absorbed from the human intestine, excellent blood levels of free AzUR have been produced that, indeed, are better maintained than those re sulting from the intravenous administration of equivalent amounts of free AzUR. With respect to toxicity of orally administered triacetyl-AzUR, four patients in an initial series displayed typical central nervous system effects, attributable on the basis of past experience to the presence of a com pound similar to 6-azauracil. In this first batch of tiiacetyl-AzUR there was a sufficient amount of freeAzUR, whichpresumablywasbrokendown by microorganisms in the gastrointestinal tract, with the release of absorbable azauracil, to cause the reversible neurotoxicity seen. In the new batch of triacetyl-AzUR that has been produced, Dr. Calabresi indicated that no toxicity had been observed thus far and requested comments from Dr. Frei and Dr. Holland. DR. FREI stated that triacetyl-AzUR had been administered orally in nine trials in six patients with chronic myelocytic leukemia. The maximum dose per day was 360 mg/kg, the molar equivalent of 240 mg. of …