Pyrazine diazohydroxide (PZDH) is a novel
antitumor agent that forms
DNA adducts via the reactive
pyrazine diazonium ion. In a recent Phase I study of PZDH, we identified a recommended Phase II dose of 100 mg/m2/day x 5, given as a 5-min i.v. bolus with the cycles repeated every 42 days (N. J. Vogelzang, et al,
Cancer Res., 54: 114-119, 1994). There was a moderate negative correlation between serum
chloride concentration and logarithm platelet nadir, suggesting the hypothesis that PZDH is activated in an acidic environment, leading to more toxicity in acidotic patients. Therefore, the University of Chicago Phase II cooperative network conducted two Phase II studies of PZDH in
renal cancer (15 patients, 2 with liver
metastases) and in 5-fluorouracil-refractory
colorectal cancer (14 patients, 13 with liver
metastases) to determine efficacy in each disease and to correlate safety and tolerance of the
drug with PZDH pharmacokinetics/pharmacodynamics and with arterial blood gas measurements. There were no responses seen in either
tumor type. The primary toxicity of PZDH was myelosuppression with
neutropenia (absolute neutrophil count, < 1000/microl) and
thrombocytopenia (<50,000 cells/microl), seen in 41 and 24% of all cycles, respectively. Other grade 3 and 4 toxicities were rare. Pharmacodynamic analysis revealed no significant correlation between plasma levels at 5, 60, and 120 min; WBCs; absolute neutrophil and platelet count nadirs; and initial serum
chloride or blood pH levels. The colorectal patients experienced significantly more
thrombocytopenia than did the
renal cancer patients (median platelet nadir after cycle 1 was 151 x 10(3)/microl for renal patients versus 76 x 10(3)/microl for colon patients; P = 0.04), suggesting either that prior
5-fluorouracil and
leucovorin reduced bone marrow reserve or that colorectal patients with liver
metastases experienced more PZDH toxicity. Regression analyses revealed a possible relationship (P = 0.06) between serum pH and
thrombocytopenia (i.e., for each increase of 0.03 in pH, there was a 34% increase in the platelet nadir), but there was no relationship between serum
chloride and
thrombocytopenia. Curiously, an increase in
alkaline phosphatase was associated with an increase in the platelet nadir (P = 0.02). If PZDH continues to be developed as an
antineoplastic agent, further studies of these relationships are suggested.