Sesquiterpene lactones: Mechanism of antineoplastic activity; relationship of cellular glutathione to cytotoxicity; and disposition
Helenalin, a sesquiterpene lactone, inhibited the growth of P388 lymphocytic and L1210 lymphoid leukemia, and Ehrlich ascites and KB carcinoma cells. The L1210 leukemia cells were most sensitive to the cytotoxic effects of helenalin. Helenalin's antineoplastic effects were due to inhibition of DNA synthesis by suppressing the activities of enzymes involved in this biosynthetic pathway; i.e., IMP dehydrogenase, ribonucleoside diphosphate reductase, thioredoxin complex, GSH disulfide oxidoreductase and DNA polymerase {alpha} activities. The relationship of reduced glutathione (GSH) to the cytotoxic effects of helanalin was evaluated. L1210 cells, which were more sensitive to helenalin's toxicity, contained lower basal concentrations of GSH. Helenalin decreased the concentration of reduced glutathione in both L1210 and P388 leukemia cells. Concurrent administration of helanalin with agents reported to raise GSH concentrations did not substantially effect GSH levels, nor were survival times of tumor-bearing mice enhanced. Following intraperitoneal administration of {sup 3}H-plenolin, no radioactive drug and/or metabolite was sequestered in the organs of BDF{sub 1} mice. Approximately 50% of {sup 3}H-plenolin and/or its metabolites were eliminated via urine while lesser amounts of radioactive drug and/or metabolites were eliminated in the feces.
- Research Organization:
- North Carolina Univ., Chapel Hill, NC (USA)
- OSTI ID:
- 5400142
- Resource Relation:
- Other Information: Thesis (Ph. D.)
- Country of Publication:
- United States
- Language:
- English
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59 BASIC BIOLOGICAL SCIENCES
GLUTATHIONE
BIOCHEMICAL REACTION KINETICS
TERPENES
TOXICITY
TUMOR CELLS
GROWTH
BIOLOGICAL PATHWAYS
DNA POLYMERASES
DNA REPLICATION
ENZYME ACTIVITY
INHIBITION
LACTONES
LEUKEMIA
MICE
OXIDOREDUCTASES
SURVIVAL CURVES
TRACER TECHNIQUES
TRITIUM COMPOUNDS
ANIMAL CELLS
ANIMALS
DISEASES
DRUGS
ENZYMES
ESTERS
HEMIC DISEASES
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
IMMUNE SYSTEM DISEASES
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
NEOPLASMS
NUCLEIC ACID REPLICATION
NUCLEOTIDYLTRANSFERASES
ORGANIC COMPOUNDS
PEPTIDES
PHOSPHORUS-GROUP TRANSFERASES
POLYMERASES
POLYPEPTIDES
PROTEINS
RADIOPROTECTIVE SUBSTANCES
REACTION KINETICS
RODENTS
TRANSFERASES
VERTEBRATES
560300* - Chemicals Metabolism & Toxicology
550201 - Biochemistry- Tracer Techniques
550901 - Pathology- Tracer Techniques