Effects of 5-fluorouracil on the cell kinetic and growth parameters of hepatoma 3924A

The effect of 5-fluorouracil (5-FU) on the growth and cellular proliferation of hepatoma 3924A was studied using the following parameters as indices of tumour response: (1) volume measurements, (2) cell kinetic analysis including estimates of both growth and cell loss fractions, (3) changes in tumour histology and (4) tumour DNA content and DNA synthesis. Of a series of single intraperitoneally injected doses (25-300 mg/kg body weight), 150 mg/kg interrupted tumour growth most effectively with minimal toxicity within 168 h, and after 10 days treated tumour volumes were only 42% of untreated tumour size. Doses of 25 mg/kg failed to change the rate of growth while 300 mg/kg exceeded the LD50. Alterations of both tumour cell proliferation and histology developed well in advance of changes observed in growth. A dose of 150 mg/kg body weight blocked the transition of cells from G1 through S for a 24 h interval when cell kinetics were measured by 3H-TdR autoradiography. However, 3H-UdR incorporation into DNA following 5-FU suggested that cellular recovery from the drug was delayed for an additional 24 h. Concurrently, significant losses of tumour tissue and tumour DNA occurred during the first 48 h with an expected increase in both necrotic and connective tissue. During the subsequent 120 h both tumour and necrotic tissue had returned to non-treated levels, while kinetic analysis revealed (a) a slight reduction in the cell cycle time and growth fraction and (b) an increased cell loss factor. The observations from this tumour model system suggest that before using tumour volume or weight as an index of therapeutic response, the relationship between the kinetics of tumour cellularity and tumour volume must be defined.