Phase I study of low-dose cyclophosphamide and recombinant interleukin-2 for the treatment of advanced cancer.

We conducted a phase I study of low-dose cyclophosphamide and recombinant interleukin-2 (rIL-2) in 66 patients with advanced cancer resistant to standard therapy. All patients were evaluable for toxicity and 46 patients were evaluable for antitumor response. Patients evaluable for antitumor response included 23 with malignant melanoma, 10 with renal cell carcinoma, 4 with colon cancer, and 9 with various other solid tumors. All patients received i.v. cyclophosphamide (350 mg/m2) on day 1 followed by rIL-2 via 15 min i.v. infusion on days 4-8 and 11-15. The doses of rIL-2 ranged from 6.0 to 36.0 x 10(6) IU/m2. Each treatment cycle consisted of 21 days and a total of 113 cycles was administered. The number of treatment cycles administered per patient ranged from 1 to 8. The dose-limiting toxicities associated with rIL-2 included altered mental status, arthralgias, diarrhea, fatigue, fever, hypotension, nausea/vomiting, and peripheral edema. Twelve patients (18%) were removed from the study secondary to toxicity. Among the evaluable patients, 2 (4%) (malignant melanoma, renal cell carcinoma) developed a partial remission, 13 (29%) maintained stable disease, and 31 (67%) developed progressive disease. We conclude that the combination of low-dose cyclophosphamide and rIL-2 is tolerable in most patients but our data do not suggest an improved response rate for the combination vs. rIL-2 alone.

Adenosine kinase-deficient mutant of Neurospora crassa.

Tubercidin-resistant mutant strains of Neurospora crassa were isolated, and at least one appeared to be deficient in adenosine kinase. No significant differences in [8-14C]adenosine labeling of purine nucleotides or nucleosides were found between the wild type and the adenosine kinase-deficient strains.

Specificity of uracil uptake in Neurospora crassa.

The specificity of uracil uptake was investigated in germinating wild-type conidia of Neurospora crassa. From comparative inhibition studies, several generalizations concerning the specificity of uracil uptake can be made. (i) The tautomeric forms of uracil analogs is an important determinant of recognition by the uptake system. (ii) Substituents at the 5 position of the pyrimidine ring may impose steric constraints on binding. (iii) The presence of a negative charge results in the loss of recognition. (iv) The double bond between the 5 and 6 carbons appears to be important for recognition. (v) Purine bases do not inhibit uracil uptake. Crude extracts of the transport-deficient mutant strain uc-5 pyr-1 were shown to have uridine 5'-monophosphate pyrophosphorylase activity comparable to that of the wild-type strain, suggesting that uracil uptake in Neurospora does not occur by a group translocation mechanism involving phosphoribosylation. Specificity studies of uridine 5'-monophosphate pyrophosphorylase indicated that phosphoribosylation was not an important determinant of the specificity of uracil uptake.