Comparison between triple therapy with octreotide, galanin and serotonin vs. irinotecan or oxaliplatin in combination with 5-fluorouracil/leukovorin in human colon cancer.

Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.

Effects of triple treatment with octreotide, galanin and serotonin on a human pancreas cancer cell line in xenografts.

Human pancreas cancer cells were implanted s.c. in nude mice. After 11 days, the mice were divided into two groups of 13. The first group received sterile saline solution and the second received triple therapy containing octreotide, galanin and serotonin, 40 microg/kg/day as a continuous i.p. infusion via an implanted osmotic pump for 14 days. Triple therapy prolonged the survival rate of the mice bearing human pancreatic carcinoma. Both the volume and weight of tumours in mice given triple therapy were less than in controls (not statistically significant). The proliferation index and the labelling index for epidermal growth factor (EGF) increased significantly in mice given triple therapy vis-a-vis controls. There was no statistically significant difference between control and treated tumours as regards, apoptotic index, necrosis, or number of tumour blood vessels. The increased survival rate was attributed to the reduced tumour load, since both weight and volume were reduced. It is most probable that octreotide was the responsible agent. Further investigation with single and double combinations of octreotide, galanin and serotonin are needed to identify the cause of increased cell proliferation in tumours subjected to these bioactive substances. Identifying the agent(s) inducing pancreatic cancer cell proliferation may be useful in combining a new treatment, as antagonists to these bioactive substances are available.

Effects of single, double or triple combinations of octreotide, galanin and serotonin on a human pancreatic cancer cell line.

The human pancreatic cancer cell line (SW 1990) was exposed to 0.2 microg/ml of octreotide, galanin or serotonin as single, double or triple combinations. The tumor cells were checked at 3, 6 and 12 hours. In order to determine the number of viable cancer cells, the MTT-assay was used. Proliferation, apoptosis and the expression of epidermal growth factor were detected with immunohistochemistry using the avidin-biotin complex method. In addition, apoptosis was also detected with (TUNEL) method. The primary antibodies used were proliferating cell nuclear antigen (PCNA), anti-poly (ADP-ribose) polymerase (PARP) and anti-human epidermal growth factor. Single treatment with octreotide or serotonin reduced, the number of viable cells and the proliferation index at all observation times. Galanin increased the number of viable cells and the proliferation index. Whereas double treatments containing octreotide reduced the number of viable cells, those containing galanin increased the number. The effect of single, double or triple treatment on the apoptotic index obtained with both TUNEL method and PARP expression varied depending on the combination and the observation time. Octreotide did not affect the tumor cell expression of EGF. Galanin and serotonin, on the other hand, increased the expression of EGF. Whereas triple combination increased the expression of EGF after 6 h, all the other double combinations decreased this expression. It has been concluded that treatment with a combination of octreotide and serotonin may be useful in clinical settings.