Selective augmentations of intratumoral 5-fluorouracil concentration by local immunotherapy with OK-432 and fibrinogen.
OBJECTIVE
Pyrimidine nucleoside phosphorylase is an enzyme that converts 5'-deoxy-5-fluorouridine into its active metabolite, 5-fluorouracil. In colorectal cancer tissue pyrimidine nucleoside phosphorylase has been proven to be produced by macrophages in the cancer stroma despite presence of the cancer cells. We reported that local immunotherapy with OK-432 and fibrinogen induced aggregation of macrophages in the cancer stroma and enforced their pyrimidine nucleoside phosphorylase expression. Thus it was hypothesized that if colon cancer were treated with 5'-deoxy-5-fluorouridine, the 5-fluorouracil concentration in cancer tissues would be enhanced by local immunotherapy. The present study was conducted to investigate whether local immunotherapy for colon cancer could increase the intratumoral 5-fluorouracil concentration in patients given chemotherapy with 5'-deoxy-5-fluorouridine.


METHODS
Twenty patients with resectable colorectal cancer were examined in this study. They were given 5'-deoxy-5-fluorouridine (600 mg/day) orally for seven days preoperatively. Nine randomly selected patients underwent intratumoral injection of OK-432 mixed with fibrinogen, which was performed on the third preoperative day (OK-432 and fibrinogen plus 5'-deoxy-5-fluorouridine group); eleven patients were given oral 5'-deoxy-5-fluorouridine only (5'deoxy-5-fluorouridine group). The 5-fluorouracil concentration in tumor tissue and normal colon mucosa tissue was measured, and the influence of the local immunotherapy was assessed.


RESULTS
The 5-fluorouracil concentration in the cancer tissue was increased by the local immunotherapy, whereas that in the normal colon mucosa was not influenced. Thus, the influence of local immunotherapy was selective to the cancer tissue where the mixture of OK-432 and fibrinogen was injected.


CONCLUSIONS
In patients with colorectal cancer, selective high 5-fluorouracil concentration in the cancer tissue could be achieved by a combination of 5'-deoxy-5-fluorouridine and local immunotherapy with a mixture of OK-432 and fibrinogen.
Amano
M
M
Department of Surgery II, Osaka University Medical School, Japan.
Sekimoto
M
M
Monden
T
T
Tomita
N
N
Ohue
M
M
Haba
A
A
Sakita
I
I
Tamaki
Y
Y
Monden
M
M
D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017024:Chemotherapy, Adjuvant; D003106:Colon / Q000473:pathology; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000601:surgery; D003131:Combined Modality Therapy; D004357:Drug Synergism; D005260:Female; D005340:Fibrinogen / Q000008:administration & dosage*; D005467:Floxuridine / Q000008:administration & dosage*; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D010844:Picibanil / Q000008:administration & dosage*; D012007:Rectum / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D005467:Floxuridine; D010844:Picibanil; D005340:Fibrinogen; D005472:Fluorouracil; C025034:doxifluridine