Toxicity and Clinical Trial of Azaserine and 6-Thioguanine in Advanced Solid Malignant Neoplasms

6-Thioguanine: A Drug With Unrealized Potential for Cancer Therapy

“…Third, although MTA/6-MP might be expected to substitute for MTA/6-TG in the method described, it does not, perhaps because 6-MP is not as potent as is 6-TG or for other reasons that are not yet known (unpublished data).The optimal dosage and schedule for in vivo experiments with the MTA/6-TG method Based on a study showing enhanced antitumor effects when mice bearing a transplanted sarcoma-180 tumor were treated with the combination of 6-TG and azaserine, a potent inhibitor of the first step in purine biosynthesis [49], two clinical studies tested this combination, one in multiple myeloma [50] and the other in patients with advanced solid tumors [51]. Results were disappointing.…”

“…Based on a study showing enhanced antitumor effects when mice bearing a transplanted sarcoma-180 tumor were treated with the combination of 6-TG and azaserine, a potent inhibitor of the first step in purine biosynthesis [49], two clinical studies tested this combination, one in multiple myeloma [50] and the other in patients with advanced solid tumors [51]. Results were disappointing.…”

Metabolism and action of amino acid analog anti-cancer agents

“…The drug was administered orally as a single agent at doses of 3 12 mg/kg daily for 5 to 20 days. Holland et al (1967) reported Hayes et al, 1967Hayes et al, 1974Schroeder et al, 1964Burchenal et al, 1955Burchenal et al, 1956Heyn et al, 1960Heyn et al, 1960Leventhal et al, 1970Leventhal et al, 1970Leventhaland Henderson, 1971LeventhalandHenderson, 1971 *Azaserine generally given in divided doses, often with oral bicarbonate.…”

“…Toxicity included anorexia, epigastric distress, nausea and vomiting, stomatitis, myelosuppression, malaise, weakness, jaundice and electrolyte disturbances. Although modest activity was seen with azaserine plus 6-thioguanosine against solid tumors, toxicity was severe (Schroeder et al, 1964). A randomized trial in acute leukemia comparing azaserine plus 6-MP versus 6-MP alone failed to demonstrate an advantage of the combination (Heyn et al, 1960).…”

Purine Antagonists

“…Azaserine was tested orally in the treatment of multiple myeloma without benefit (Holland et at., 1961). Azaserine was used in combination with thioguanine, both given intravenously (Schroeder et at., 1964). Of 7 breast carcinoma patients, 4 showed improvement; 1 with squamous-cell carcinoma showed improvement, and 11 were unresponsive.…”