A Phase II Trial of Pyrazine Diazohydroxide in Patients with Disseminated Malignant Melanoma and no Prior Chemotherapy – Southwest Oncology Group Study

Abstract

Malignant melanoma is rapidly increasing in the United States. Metastatic disease responds poorly to currently available chemotherapy. Pyrazine diazohydroxide (PZDH) is a new agent inhibiting DNA synthesis that is active in mouse tumor models and human xenografts and lacks cross resistance with multiple standard agents. In this phase II trial, patients with no prior chemotherapy or immunotherapy for metastatic disease and performance status (SWOG) of 0-1, were treated with pyrazine diazohydroxide at a dose of 100 mg/m2/day by i.v. bolus injection over 5-15 minutes for 5 consecutive days every 6 weeks. There were 23 eligible patients entered on this trial with 74% having PS of 0 and 91% having visceral metastases. There were no confirmed anti-tumor responses. The overall response rate is 0% (95% CI 0%-15%). Median overall survival is six months (95% CI 5-8 months). The most common toxicities were hematologic and consisted of lymphopenia, thrombocytopenia, anemia, and leukopenia. Fatigue. and nausea and vomiting were the next most common toxicities. Pyrazine diazohydroxide by this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.

Palladium(II)-Stabilized Pyridine-2-Diazotates: Synthesis, Structural Characterization, and Cytotoxicity Studies

“…Interestingly, in comparison to the other complexes, 2 exhibits some degree of selectivity with a 2-fold stronger growth inhibition effect on A2780 cancer cells compared to noncancerous HEK293 cells. Over time the complexes are likely to release highly cytotoxic diazotates under physiological conditions. − It has been previously shown that diazotates interact with a number of different biomolecular targets. − ,, Because these targets are not cancer-cell-specific, the similar cytotoxicities observed in the tumorigenic and nontumorigenic cell lines studied here are not unexpected. In addition, the palladium fragment is also likely to exert a cytotoxic effect, and previous palladium­(II) complexes have been shown to bind to a number of different targets including DNA, − also rationalizing the lack of cancer cell specificity.…”

“…They are key intermediates in Gomberg–Bachmann aromatic C–H activation , and other organic processes that involve diazonium salts. − Diazotates are important from the biological perspective because they are involved in nitric oxide-induced DNA damage and are believed to be one of the reactive intermediates that form during the decomposition of N -nitrosamines . Earlier studies showed that the relatively stable sodium pyrazine-2-diazotate (half-life 44 min at pH 7) exhibited substantial activity against a number of cancers. − The low stability as well as limited number of readily available diazotates narrows the utility of this important class of compounds.…”

“…The extremely poor solubility of 5 precluded a 1 H NMR spectroscopic study. Notably, palladium-bound pyridine-2-diazotates exhibit high stability compared to the alkali-metal analogues, − , as evidenced by 1 H NMR spectroscopy (DMSO- d 6 ), which did not show any significant decomposition with measurements taken over 2 weeks at room temperature. Thermogravimetric analysis for 1 showed that it starts to decompose at ca.…”

N-Substituted 5-Amino-6-methylpyrazine-2,3-dicarbonitriles: Microwave-Assisted Synthesis and Biological Properties

“…Although PZA is the first-line antituberculotic drug, it was found that this molecule has exhibited other interesting biological activities such as antifungal, antibacterial, antiviral and antineoplastic effects [15,16,17,18,19,20].…”

New Potentially Active Pyrazinamide Derivatives Synthesized Under Microwave Conditions

“…PZA and its derivatives have also many other useful applications, as they show antiviral, antifungal, antibacterial and as well as antineoplastic activities [14,15,16,17,18,19,20]. Several pyrazine derivatives were also found to inhibit photosynthetic electron transport (PET) in plant chloroplasts [21,22,23].…”