Tricyclic
nucleoside phosphate (
TCN-P) was selected for clinical trials because of its unusual chemical structure and activity against L1210 murine
leukemia and MX-1 mammary xenograft. Inhibiting
DNA synthesis,
TCN-P was more toxic during S-phase of cell cycle. A phase I study was conducted in 24 patients with advanced solid
cancers. The
drug was given as a slow i.v. injection over 5 min on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 12 to 96 mg/m2 were studied with 3 to 12 patients treated at each level; a total of 106 doses was administered. The major hematological toxicity was
thrombocytopenia, with a median nadir occurring at Day 34 of the cycle and first appearing at doses greater than 24 mg/m2.
Anemia was seen at each dose level occurring between Days 8 and 34. Non-myelosuppressive toxic effects included
stomatitis,
anorexia, transient
fever,
nausea and
vomiting, and dose-limiting
hyperglycemia and
diarrhea. The highest tolerated dose was 48 mg/m2. Plasma, pleural fluid, urine, and tissue samples were analyzed for
TCN-P and tricyclic
nucleoside (TCN) in selected patients by high-performance liquid chromatography. Plasma decay curves revealed extended retention of both TCN and
TCN-P. Autopsy specimens obtained 61 days after
therapy showed the highest residues of
TCN-P in liver
metastases and of TCN in gall bladder, bile, and pancreas. No
drug was detected in urine samples of two patients. Prolonged retention and erratic plasma levels of the
drug are probably due to extensive enterohepatic circulation, as well as repeated interconversion between
TCN-P and TCN within cells. This weekly schedule produced unexpected clinical toxicity and should not be pursued.