Courtney M. Townsend

Differential sensitivity of pancreatic and colon cancer to cyclosporine and α-difluoromethylornithine in vivo

SummaryWe have previously reported that the in vitro growth of MC-26 mouse colon cancer and H2T hamster pancreatic cancer cells are inhibited by cyclosporine (CsA) and α-difluoromethylornithine (DFMO). The present study was designed to investigate the effects of these two drugs on the two experimental tumors (MC-26 and H2T) growing in vivo. Forty-eight male Balb/c mice or Syrian golden hamsters were inoculated with MC-26 (250,000) or H2T (500,000) cells, respectively, and then were randomized into four groups of 12 each: group I was control; group II received CsA; group III received DFMO; group IV received a combination of CsA and DFMO. MC-26 tumors were significantly more sensitive than H2T tumors to the effects of CsA and DFMO. MC-26 tumor growth and tumor weight, as well as the tumor content of DNA, RNA, and protein were all significantly more reduced by CsA and DFMO than were the H2T tumors. Our present study shows that both CsA and DFMO are potent inhibitors of MC-26 colon carcinoma growth in vivo, though DFMO is more than twice as effective as CsA. DFMO also produced greater reductions in the tumor content of DNA, RNA, and protein than did CsA. DFMO significantly decreased the concentrations of polyamines in both H2T and MC-26 tumors; the MC-26 tumors were affected to a greater degree.

Schedule dependent potentiation of antitumor drug effects by α-difluoromethylornithine in human gastric carcinoma cells in vitro

SummaryA clone of human gastric cancer cells (AGS-6) and the parental line (AGS-P) from which it was isolated were used in cell survival studies to determine whether pretreatment for 24, 48 or 72h with α-difluoromethylornithine (DFMO, 5mM) would increase the cells sensitivity to 5-Fluorouracil (5FU), Adriamycin (Adria), 1-(2-chloroethyl)-3-(4-methyl cyclohexyl)-1-nitrosourea (MeCCNU), or Bleomycin (Bleo). Generally, the AGS parental cells were most sensitive to the anticancer agents after exposures to DFMO. However, there was no way to predict in advance from DFMO-induced changes in ornithine decarboxylase (ODC), polyamine or cell kinetics values, how long an exposure to DFMO was required before sensitization to an anticancer agent occurred. The degree of potentiation for a single drug was variable from time to time during exposure to DFMO, and broad differences in the sensitizations were demonstrated among the four anticancer drugs. The AGS-6 clone exhibited little or no increased sensitivity as a result of pretreatment with DFMO, even though the DFMO-induced reductions in ODC and polyamine values in these cells were similar to those produced in the more sensitive parental line.

Insulin-Like Growth Factors and Their Receptors and Binding Proteins in the Gastrointestinal System

Insulin-like growth factor I and II (IGF-I, and IGF-II) are single chain peptides with around 70% sequence homology and 50% homology with proinsulin The IGFs were first identified in 1956 and were originally named sulfation factors or somatomedins (1, 2). IGF circulating in the blood at concentrations of 20–80 nM is mainly produced by the liver; whereas tissue IGF is produced, in great part, locally. The expression of IGF-I and, to a lesser degree, of IGF-II in the human liver is under the control of growth hormone (GH). IGF-I can mimic most, but probably not all, the effects of GH. IGFs, their receptors and their binding proteins, constitute a family of cell modulators that play essential roles in the regulation of growth and development. The IGFs interact with specific receptors designated as type I and type II IGF receptors, as well as with insulin receptors. Most, if not all, of the mitogenic effects of IGFs are mediated via type I IGF receptors. The biological roles of IGFs are modulated by a family of at least six binding proteins (IGFBPs) that are found in the circulation, and in extracellular compartments and produced by most tissues (3–6).