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Flavone acetic acid (NSC 347512)-induced DNA damage in Glasgow osteogenic sarcoma in vivo
M C Bissery1, F A Valeriote, G G Chabot
1Department of Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201.
Abstract:
Flavone acetic acid (FAA) is a new antitumor agent with broad activity against transplantable solid tumors of mice but with only scant or no activity against leukemias and lymphomas. The technique of alkaline elution was used to study DNA lesions in s.c. implanted Glasgow osteogenic sarcoma in C57BL/6 x DBA/2 F1 mice treated i.v. with FAA. At efficacious dosages (235 and 200 mg/kg), FAA produced extensive single strand breakage. Formation of single strand breaks was dependent on time of assay after exposure to FAA with only minimal damage occurring prior to 5 h posttreatment. Apparently Glasgow osteogenic sarcoma had no capacity to repair single strand breaks for at least 45 h after drug administration. Thus, FAA differs in its mechanism from other scission agents (e.g., VP-16). Neither interstrand cross-links nor DNA-protein cross-links were detected. DNA single strand breaks did not occur in the bone marrow cells or in the unresponsive P388 leukemia cells at dosages causing extensive DNA damage in solid tumor cells.
Insights
Flavone acetic acid (FAA) causes significant DNA single-strand breaks in solid tumors, but not in leukemias. This antitumor agent shows limited repair capacity in tumor cells, distinguishing its mechanism from other DNA-damaging drugs.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Flavone acetic acid (FAA) is an antitumor agent effective against solid tumors but not leukemias or lymphomas.
- Understanding the mechanism of action of FAA is crucial for its therapeutic development.
Purpose of the Study:
- To investigate the DNA damage induced by Flavone acetic acid (FAA) in solid tumor cells.
- To compare the DNA damage response in tumor cells versus non-responsive leukemia cells and bone marrow cells.
Main Methods:
- Utilized alkaline elution technique to assess DNA lesions in Glasgow osteogenic sarcoma cells in mice treated with FAA.
- Quantified DNA single-strand breaks, interstrand cross-links, and DNA-protein cross-links at various time points post-treatment.
Main Results:
- Efficacious doses of FAA (200-235 mg/kg) induced extensive DNA single-strand breaks in solid tumor cells.
- DNA damage was time-dependent, with minimal breaks occurring before 5 hours post-treatment.
- Glasgow osteogenic sarcoma cells exhibited limited capacity to repair DNA single-strand breaks for at least 45 hours.
- No significant DNA single-strand breaks were observed in bone marrow or P388 leukemia cells at dosages causing extensive damage in solid tumors.
- Neither interstrand nor DNA-protein cross-links were detected.
Conclusions:
- Flavone acetic acid (FAA) primarily induces DNA single-strand breaks in susceptible solid tumors.
- The limited DNA repair capacity in tumor cells suggests a potential therapeutic window for FAA.
- FAA's mechanism, distinct from other DNA scission agents, warrants further investigation for antitumor drug development.