Dinaline inhibits amino acid transport and proliferation of colon carcinoma cells in vitro.
The human colon carcinoma cell line SW707 was incubated with different concentrations (7 microM - 540 microM) of the novel antineoplastic drug 4-amino-N(2'-aminophenyl)benzamide (GOE1734, dinaline) to study the effects on 3H-alpha-aminoisobutyric acid (AIB) - and 14C-methionine uptake as well as on 3H-thymidine incorporation into DNA. Additionally, adenine nucleotide pools were determined by high performance liquid chromatography (h.p.l.c.), and cell cycle distribution by flow cytometry. 24 h exposure to low concentrations of dinaline caused mild cell proliferation which turned into a cytostatic effect within a further 24 h without drug exposure. High concentrations of dinaline, however, were found to be cytostatic and then cytotoxic after corresponding time intervals. Dinaline caused a concentration-dependent decrease in sodium-dependent AIB uptake. Immediately after exposure the effect ranged from 67%-36% of control uptake. One day later an incomplete recovery not exceeding 70% of control was found for the three highest concentrations. This differed significantly from sodium-dependent methionine uptake which was initially decreased by 24%-36% but recovered within one hour and was enhanced one day after exposure. Significant differences were also measured for sodium-independent AIB uptake and sodium-independent methionine uptake immediately, 1 and 4 h after exposure. Adenine nucleotide pools were mildly increased immediately and 4 h after exposure. Thymidine incorporation into DNA was decreased by 70% to 84% immediately after exposure, and no full recovery was seen in the subsequent observation period. Cell cycle analyses revealed a block at the S phase entrance. Changes in thymidine incorporation and S phase fraction were highly correlated. The inhibition of the sodium-dependent uptake of AIB might indicate interaction of dinaline with cell membrane functions at low concentrations, the increase in methionine uptake points to enhanced protein synthesis following drug withdrawal and the impaired thymidine incorporation into DNA results from the cytostatic effect of dinaline. Taken together, the results show that SW707 colon carcinoma cells exposed to dinaline demonstrate distinct but reversible changes in amino acid transport, protein metabolism, DNA synthesis and cell proliferation, thus giving a correlation with observations in vivo.
Schaider
H
H
Unit of Toxicology and Chemotherapy, German Cancer Research Center, Heidelberg, F.R.G.
Haberkorn
U
U
Stöhr
M
M
Berger
M R
MR
D000227:Adenine Nucleotides / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000621:Aminoisobutyric Acids / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D004261:DNA Replication / Q000187:drug effects; D004273:DNA, Neoplasm / Q000096:biosynthesis; D003864:Depression, Chemical; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D008715:Methionine / Q000378:metabolism; D010655:Phenylenediamines / Q000494:pharmacology*; D012964:Sodium / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000227:Adenine Nucleotides; D000596:Amino Acids; D000621:Aminoisobutyric Acids; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D006131:Growth Inhibitors; D010655:Phenylenediamines; C100049:2-aminoisobutyric acid; D012964:Sodium; D008715:Methionine; C045838:dinaline