Multi-enzyme-targeted chemotherapy by acivicin and actinomycin

Area of Science:

• Biochemistry
• Pharmacology
• Oncology

Background:

• Glutamine-utilizing enzymes are crucial for purine and pyrimidine metabolism.
• Hepatoma cells exhibit altered glutamine metabolism compared to normal liver cells.

Purpose of the Study:

• To investigate the biochemical pharmacology of acivicin, an anti-glutamine agent.
• To determine acivicin's effect on glutamine-utilizing enzymes in liver and hepatoma.

Main Methods:

• Enzyme activity assays using liver and hepatoma extracts.
• In vitro and in vivo studies of acivicin's inhibitory and inactivating effects.
• Combination chemotherapy studies with acivicin and actinomycin.

Main Results:

• Acivicin competitively inhibited amidophosphoribosyl-transferase, CTP synthetase, and carbamoyl-phosphate synthetase II.
• Acivicin irreversibly inactivated these glutamine-utilizing enzymes in vitro and in vivo.
• Aspartate carbamoyltransferase activity remained unaffected, indicating selectivity.
• Acivicin and actinomycin demonstrated synergistic effects on hepatoma cell kill and tumor growth inhibition.

Conclusions:

• Acivicin acts as a potent inhibitor and inactivator of key enzymes in nucleotide synthesis.
• Acivicin's selective action on glutamine-utilizing enzymes offers therapeutic potential.
• Combination therapy with acivicin and actinomycin shows promise for cancer treatment.