Abstract
We have demonstrated that urinary trypsin inhibitor (UTI) purified from human urine is able to inhibit lung metastasis of mouse Lewis lung carcinoma (3LL) cells in experimental and spontaneous metastasis models. In this study, we have investigated whether UTI in combination with an anti-cancer drug, etoposide, can prevent tumour metastasis and show an enhanced therapeutic effect. Subcutaneous (s.c.) implantation of 3LL cells (1 x 10(6) cells) in the abdominal wall of C57BL/6 female mice resulted in macroscopic lung metastasis within 21 days. Microscopic lung metastasis was established by day 14 after tumour cell inoculation, and surgical treatment alone after this time resulted in no inhibition of lung metastasis. The number of lung tumour colonies in the group of mice which received surgery at day 21 was greater than in mice which had tumours left in situ (P = 0.0017). Surgical treatment on day 7, followed by UTI administration (s.c.) for 7 days, led to a decrease in lung metastasis compared with untreated animals. A significant inhibition of the formation of pulmonary metastasis was obtained with daily s.c. injections of UTI for 7 days immediately after tumour cell inoculation. UTI administration did not affect the primary tumour size at the time of operation. In addition, etoposide treatment alone led to a smaller primary tumours and yielded reduction of the formation of lung metastasis in the group of mice which received surgery at day 14 (P = 0.0026). Even in mice which received surgical treatment on day 14, followed by the combination of UTI (500 micrograms per mouse, days 14, 15, 16, 17, 18, 19 and 20) with etoposide (40 mg kg-1, days 14, 18 and 22), there was significant reduction of the formation of lung metastasis (P = 0.0001). Thus, the combination of an anti-metastatic agent with an anti-cancer drug, etoposide, might provide a therapeutically promising basis for anti-metastatic therapy.
Highlights
Etoposide treatment alone led to smaller primary tumours and yielded reduction of the formation of lung metastasis in the group of mice which received surgery at day 14 (P= 0.0026)
Microscopic lung metastasis was established by day 14 after tumour cell inoculation, and surgical treatment alone after this time resulted in no inhibition of lung metastasis
We demonstrated that Urinary trypsin inhibitor (UTI) inhibited production of experimental and spontaneous pulmonary metastasis by murine Lewis lung carcinoma (3LL) cells (Kobayashi et al, 1995a)
Summary
A murine 3LL cell line, selected for its high lung colonisation potential, was maintained by serial s.c. transplantation in C57BL/6 mice. The surgical excision of primary tumour was performed on various days. The number of lung tumour colonies of the animals given s.c. injections of tumour cells and treated with (Figure lb, c and d) and without operation (Figure la) was determined. Mouse abdominal wall UTI was administered and s.c. allowed to on various grow days immediately after tumour cell inoculation and/or after the surgical excision of primary tumour on day 14. The surgical excision of primary tumour was not performed; (b) control 2 (injection of vehicle). Vehicle); surgical excision was (a) not performed; (b) control 2 (injection of vehicle), surgery was performed on day 7 Surgery was Number of performed on lung tumour day 14 and multiple injections of colonies (mean ± s.d): (a) 56.64.
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