The synergistic and antagonistic effects of cytotoxic and biological agents on the in vitro antitumour effects of suramin.
Suramin has shown antitumour activity in vitro and in vivo. At plasma levels higher than 200 microM there is, however, excessive toxicity. We have, therefore, attempted to improve the antitumour effects of suramin in vitro by combining it with several other antitumour agents. The MCF-7 mammary carcinoma and PC3 prostate cancer cell lines were exposed continuously to suramin and the other agents for 6 days. The sulphorhodamine B (SRB) assay was used for the assessment of growth inhibition. The dose-response interactions were evaluated using the median-effect analysis with the Chou and Talalay computer programme. In the MCF-7 cell line, the combination of suramin plus doxorubicin (DXR), cisplatin (CDDP), 5-fluorouracil (5-FU) or tumour necrosis factor (TNF) resulted in synergistic growth inhibition, whilst its combination with miltefosine (HPC) was antagonistic. In the PC-3 cell line, suramin plus CDDP or TNF was synergistic, whilst its combination with DXR, 5-FU and HPC was antagonistic. All tested combinations with interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma) and with the combination of both IFN-alpha+IFN-gamma were not synergistic. The synergistic effect of suramin with DXR was schedule dependent. Pretreatment (addition of DXR on day 1 and suramin on days 2-5) was additive at the IC50 level, in both cell lines. Addition of DXR at day 5 was more effective than simultaneous exposure. We found a synergistic effect for the combination of suramin with CDDP and TNF in both cell lines. In addition the combination with DXR and 5-FU was synergistic in MCF-7. Sequential administration of DXR-suramin or suramin-DXR increased the growth inhibition.
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
R
R
Lopez Lopez
R E
RE
van Rijswijk
J
J
Wagstaff
H M
HM
Pinedo
G J
GJ
Peters
D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008297:Male; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D010767:Phosphorylcholine; C039128:miltefosine; D013498:Suramin; D004317:Doxorubicin; D002945:Cisplatin; D005472:Fluorouracil