[Pharmacological and biochemical investigation of intracavital fluorinated pyrimidine chemotherapy].
We investigated the biochemical and molecular pharmacological parameters of fluorinated pyrimidines using malignant cells in pleural effusion or ascites from patients with malignant disease both before and after fluorinated pyrimidine chemotherapy, either systemically or intravesically. In four out of fifteen cancer patients, we could analyze the alteration of thymidylate synthase (TS) catalytic activity both before and after the treatment, showing that there was a decrease ranging 28% through 96.9%. We also analyzed a level of TS messenger RNA and TS protein using molecular biotechniques. None of these mutual correlations has so far been demonstrated, indicating that the data were analyzed through samples from patients not responding to the fluorinated pyrimidines. In a responding patient with advanced breast cancer, pre-treatment total TS protein was 130 fmol/mg and the TS activity was 3.27 pmol/mg/min. After intrapleural instillation of a combination of 5-FU 250 mg and leucovorin 3 mg, the total amount and the catalytic activity of TS could be measured. On the 11th day of treatment, the TS protein level decreased to 26 fmol/mg and the TS catalytic activity also decreased to 0.1 pmol/mg/min resulting in a TS inhibition rate of 92.3 percent. On the 17th day, the patient's malignant pleural effusion disappeared almost completely, suggesting that substantial TS inhibition may reflect the clinical evidence. This particular data showed that it would be predictable for clinical outcome to evaluate these parameters before and after fluorinated pyrimidine chemotherapy. Further study is warranted to evaluate the exact role of analyzing these parameters in clinical practice.
Shibata
H
H
Dept. of Medical Oncology, Cancer Institute Hospital, Japanese Foundation for Cancer Research.
Aiba
K
K
Mihara
H
H
Ito
Y
Y
Takahashi
S
S
Horikoshi
N
N
Kasumi
F
F
Ohta
H
H
Takahashi
T
T
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000494:pharmacology; D001202:Ascitic Fluid / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D001943:Breast Neoplasms / Q000150:complications*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D016066:Pleural Effusion, Malignant / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology; D012333:RNA, Messenger / Q000378:metabolism; D013940:Thymidylate Synthase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000964:Antimetabolites, Antineoplastic; D012333:RNA, Messenger; D013940:Thymidylate Synthase; D005472:Fluorouracil