Inhibition by interleukin 18 of osteolytic bone metastasis by human breast cancer cells.
Effects of interleukin (IL)-18 on experimental bone metastasis of human breast cancer cells, MDA-231 cells, in nude mice were investigated. In addition, effects of IL-18 on subcutaneous growth of MDA-231 cells were examined. Bone metastasis was produced by an intracardiac injection of MDA-231 cells. Twenty eight days after the cell injection, severe osteolytic bone metastasis was examined by X-ray radiography, and both non-osteolytic and osteolytic bone metastases were examined microscopically. IL-18 (1 microgram/mouse) was injected intraperitoneally according to protocols A and B. In protocol A, IL-18 was injected daily from day 7 after an intracardiac or subcutaneous injection of cells, and in protocol B, it was injected daily for 7 days each before and after the cell injection. In protocol A, IL-18 injections significantly suppressed both the incidence of osteolytic bone metastasis detected by X-ray radiography (about 80% vs. about 20% for the control group vs. the treatment group) and the number of its foci/mouse (1.6 vs. 1 for the control group vs. the treatment group). However, they did not cause significant effects on either the incidence of bone metastasis detected microscopically or the number of its foci/mouse. In protocol B, IL-18 injections caused no significant effects on either the incidence of osteolytic bone metastasis detected by X-ray radiography or the number of its foci/mouse. They caused no significant effects on the incidence of bone metastasis detected microscopically, but significantly decreased the number of its foci/mouse (about 2.0 vs. about 1 for the control group vs. the treatment group). In both protocols A and B, IL-18 injections produced no significant effect on the tumor take and subsequent growth of tumors after a subcutaneous injection of the cancer cells. Since in protocol A, IL-18 appears to have exerted its action after establishment of metastasis by cancer cells to the bone marrow, the effects of IL-18 found in Protocol A indicate that IL-18 inhibited osteolytic growth at bone metastatic sites of breast cancers. On the other hand, since in protocol B IL-18 is likely to have functioned around the time when lodging of cancer cells and early development of metastasis occur in the bone marrow, the effects of IL-18 found in Protocol B indicate that the cytokine also suppresses an early stage of bone metastasis of breast cancers, although, this effect was less apparent than the effect on osteolytic growth. Therefore, IL-18 may be useful for suppression of osteolytic bone metastasis which is a serious problem in patients of advanced breast cancers.
Nakata
A
A
Second Department of Internal Medicine, Hyogo College of Medicine, Japan.
Tsujimura
T
T
Sugihara
A
A
Okamura
H
H
Iwasaki
T
T
Shinkai
K
K
Iwata
N
N
Kakishita
E
E
Akedo
H
H
Terada
N
N
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000473:pathology / Q000517:prevention & control / Q000556:secondary*; D001943:Breast Neoplasms / Q000473:pathology*; D005260:Female; D006801:Humans; D020382:Interleukin-18 / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000187:drug effects; D010014:Osteolysis / Q000517:prevention & control*; D011859:Radiography; D011994:Recombinant Proteins / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D020382:Interleukin-18; D011994:Recombinant Proteins