Anti-sense oligonucleotides directed against EGF-related growth factors enhance anti-proliferative effect of conventional anti-tumor drugs in human colon-cancer cells.
We have demonstrated that anti-sense phosphorothioate oligodeoxynucleotides (AS S-oligos) directed against the EGF-like growth factors CRIPTO (CR), amphiregulin (AR) or transforming-growth-factor-alpha(TGFalpha) mRNA, are equipotent in their ability to inhibit the growth of human colon-carcinoma GEO cells. In this study, we evaluated the effect of combinations of these AS S-oligos and conventional anti tumor drugs, such as 5-fluorouracil (5-FU), adriamycin (ADR), mitomycin C (MIT) and cis-platinum (CDDP), on GEO cell growth. Dose-dependent growth inhibition was observed by treatment either with AS S-oligos or with anti-tumor drugs, using a clonogenic assay. Furthermore, an additive growth inhibitory effect occurred when GEO cells were exposed to the AS S-oligos after treatment with different concentrations of either 5-FU, MIT, ADR or CDDP. For example, treatment of GEO cells with a combination of low concentrations of 5-FU and any of the 3 AS S-oligos resulted in up to 70% growth inhibition. However, treatment of GEO cells with AS S-oligos before exposure to 5-FU or CDDP resulted in reduced efficacy of both drugs. Flow-cytometric analysis of DNA content demonstrated that treatment with the AS S-oligos caused a slight reduction of the percentage of cells in the S-phase of the cell cycle. These data suggest that combinations of AS S-oligos directed against EGF-related growth factors and of conventional anti-tumor drugs may result in efficient inhibition of colon-carcinoma cell growth.
De Luca
A
A
Oncologia Sperimentale D, ITN-Fondazione Pascale, Naples, Italy.
Selvam
M P
MP
Sandomenico
C
C
Pepe
S
S
Bianco
A R
AR
Ciardiello
F
F
Salomon
D S
DS
Normanno
N
N
D066258:Amphiregulin; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004273:DNA, Neoplasm / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006023:Glycoproteins / Q000235:genetics*; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D016685:Mitomycin / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D013873:Thionucleotides / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000235:genetics*; D014407:Tumor Cells, Cultured
C587848:AREG protein, human; D066258:Amphiregulin; D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004338:Drug Combinations; D066255:EGF Family of Proteins; D058851:GPI-Linked Proteins; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; C070636:TDGF1 protein, human; D013873:Thionucleotides; D016211:Transforming Growth Factor alpha; D016685:Mitomycin; D004815:Epidermal Growth Factor; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil