Effects of short term treatment with pentagastrin, proglumide, tamoxifen given separately or together with 5-fluorouracil on the growth in the murine transplantable Colon 38 cancer.

ABSTRACT

It is well known that 5-fluorouracil (5-FU) is the most effective drug in the treatment of colon cancer, however the positive response is small, only about 20%. On the other hand, it has been postulated that the growth of colon cancer depends on many growth factors, such as gastrin and estrogens. The search for new substances increasing the antitumor effect of 5-FU has lasted for many years. The aim of the present study was to examine the effects of pentagastrin (PEN, syntetic gastrin analogue), proglumide (PRO, a blocker of gastrin receptor) and tamoxifen (TAM, a partial estrogen antagonist) given separately or together with 5-FU on proliferation, apoptosis, necrosis and proliferation/apoptosis (P/A) ratio in the murine transplantable Colon 38 cancer. The male mice were implanted with a suspension of Colon 38 cells. After 7 days, the animals were treated with PEN (250 microg/kg b.w., twice daily), PRO (100 mg/kg. b.w., twice daily), TAM (10 microg/animal) separately or together with 5-FU (60 mg/kg b.w., once) for 2 days. The incorporation of bromodeoxyuridine (BrdU) into cell nuclei was used as an index of cell proliferation (labeling index--LI). The in situ labeling of nuclear DNA fragmentation according to TUNEL method was considered as an apoptotic index (AI). It was found that 5-FU increased the apoptosis, unexpectedly increased the LI and decreased the P/A ratio when compared to control. Both PEN and PRO increased the apoptosis and in the case of PRO decreased P/A ratio when compared to control. TAM did not affect any of the examined parameters. All of the investigated substances modify the 5-FU action PEN and PRO on AI and LI and TAM on AI and P/A ratio. Necrosis was observed in 3 tumors treated with PEN + 5-FU, in 2 tumors of PRO + 5-FU group and in 1 tumor of group with 5-FU and with PEN. Further studies are needed to elucidate if those modification of 5-FU action by the examined substances will be useful in the inhibition of the growth of Colon 38 cancer.