Preliminary evaluation of isocyanate-generating nitroheterocycles as chemosensitizers, radiosensitizers and hypoxic cell cytotoxic agents.

Abstract

Nitro-compounds containing an acetylated acetohydroxamic acid side chain in the N-1 position of a 5-membered ring nitrogen heterocycle have been synthesized. These compounds, which can generate isocyanates via a Lossen rearrangement, were evaluated in order to test the hypothesis that they may be effective radiation and chemosensitizing agents by nature of their isocyanate-associated carbamoylating potential. Evaluation of one such compound, DJW-77 (1(O-Acetyl-Acetohydroxamic acid)-3-nitropyrazole) as a radiation sensitizer, chemosensitizer and hypoxic cell toxin is reported. In vitro DJW-77 demonstrates a potent selective cytotoxicity toward hypoxic EMT-6 tumor cells, is an effective potentiator of CCNU toxicity and is comparable to MISO with respect to its radiation-sensitizing potential. The activity of the drug is eliminated under aerobic conditions. To test the hypothesis that the activity of DJW-77 is related to isocyanate generation, the non-acetylated analog of DJW-77 (which does not directly undergo the Lossen rearrangement) and the parent 3-nitropyrazole ring structure were evaluated. Neither compound enhanced CCNU toxicity, and on an equimolar basis were inferior to DJW-77 as radiation sensitizers. While the non-acetylated analog was cytotoxic to hypoxic cells, relative to DJW-77 this activity was substantially reduced. These studies indicate that the addition of a side chain capable of generating an isocyanate can enhance the cytotoxicity and sensitizing activity of nitroheterocycles.

• Authors: R T Mulcahy, D J Wustrow, A S Kende
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 10 Issue 9 Pg. 1609-13 (Sep 1984) ISSN: 0360-3016 [Print] United States
• PMID: 6548210 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antineoplastic Agents
• Pyrazoles
• Radiation-Sensitizing Agents
• 3-nitropyrazole
• Lomustine
• 1-(O-acetyl-acetohydroxamic acid)-3-nitropyrazole
• 1-acetohydroxamic acid-3-nitropyrazole
• Oxygen

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Survival (drug effects, radiation effects)
• Dose-Response Relationship, Drug
• Dose-Response Relationship, Radiation
• Drug Synergism
• Lomustine (pharmacology)
• Neoplasms, Experimental (pathology)
• Oxygen (physiology)
• Pyrazoles (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)