Increased growth and incidence of lymph node metastases due to the angiogenesis inhibitor AGM-1470

Abstract

Summary Using the rat tumour cell line LY80, a subline of Yoshida sarcoma, the effects of AGM-1 470 on the growth of primary tumour and the incidence of regional lymph node metastasis were evaluated. AGM-1 470 (30 mg kg-') was administered subcutaneously or intravenously. Subcutaneous (s.c.) and intravenous (i.v.) injections were repeated for 8 days and 7 days respectively. Tumour growth of a primary region tended to be suppressed by AGM-1470. The s.c. tumours after sacrifice were much smaller in the AGM-1470-treated group (s.c. injection) than in the control groups. However, the growth of metastatic foci in the lymph nodes was prompted markedly by AGM-1470. All six of the AGM-1 470-treated rats had developed swollen axillary lymph nodes and/or brachial lymph nodes on day 19 after tumour implantation (the 7th day after the last treatment) compared with one of six saline-injected rats and three of six vehicle-alone treated rats with swollen axillary lymph nodes. The weight of lymph nodes after sacrifice in the AGM-1470-treated rats was much heavier than that of the other two groups.Histological examination showed that in the AGM-1470-treated group, the cortex and the medulla of the axillary lymph nodes were almost entirely replaced by tumour cells while, in the vehicle alone group, a notable hyperplasia of the lymph nodes due to BT cell proliferation tended to be induced. In the saline group, although a slight hyperplasia of lymph nodes was observed, there were only a few lymph node metastases. In the case of i.v. injection of AGM-1470, similar results were obtained. It is thought that LY80 cells spread to regional lymph nodes at a comparatively early stage by some change or other in which AGM-1470 participated. From the present experiment, it is concluded that application of AGM-1470 alone to patients should be carried out with great caution.Keywords: angiogenesis; AGM-1470; LY80 cell; lymph node metastasis It has been reported that AGM-1470, an analogue of fumagillin isolated from Aspergillus fumigatus, inhibited tumour growth in mice and rats (Ingber et al, 1990;Yamaoka et al, 1993a;Yanase et al, 1993) and extended the survival time of animals with some kinds of tumours (Yamaoka et al, 1993b). Furthermore, in mice treated with AGM-1470, haematogenous metastasis was strongly inhibited with regard to both the number and the size of tumour nodules (Yamaoka et al, 1993b;Tanaka et al, 1995). To date, however, there have been very few studies on the effects of AGM-1470 on lymphogenous metastasis. To improve the chance of survival, it is important to inhibit not only haematogenous metastasis but also lymphogenous metastasis, because metastases to the regional lymph nodes occur very frequently in cancer patients.The purpose of the present study was to evaluate the effects of AGM-1470 on both the growth of primary s.c. tumours and the incidence of regional lymph node metastasis. Using a model of lymph node metastasis, we used the LY80 tumour cell line system, in which tumour cells spontaneously and uniformly metastasi...

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