Inhibition of growth factor mitogenicity and growth of tumor cell xenografts by a sulfonated distamycin A derivative.
Interference with growth factor-receptor interactions may have particular relevance in efforts to intervene clinically in both autocrine and paracrine aspects of malignancy. Suramin is a synthetic anticancer agent that works, in part, by blocking the binding of growth factors to their receptors. While initial clinical trials have been encouraging, its use in clinical applications is associated with significant toxicities. Suradista is a novel sulfonated distamycin derivative that is also effective at complexing and inactivating growth factors and cytokines while remaining relatively nontoxic. The goal of this study was to compare the antineoplastic properties of suramin and Suradista. To achieve this, the effects of these compounds on growth factor induced mitogenesis in normal mouse fibroblasts and human umbilical vein endothelial cells were examined, as well as their ability to inhibit the growth of NIH/3T3 cells that had been transformed by the introduction of a fibroblast growth factor (FGF) 1 coding region (residues 1-154) fused to the signal peptide of the hst/KS3 gene (sp-hst/KS3:FGF1-154). In each case, Suradista was more effective than suramin in inhibiting mitogenesis in normal cells, as well as the growth of the transformed cells. Furthermore, Suradista was also shown to be as effective as suramin at inhibiting the growth of sp-hst/KS3:FGF1-154-transformed NIH/3T3 xenografts grown in athymic nude mice when given at only 50% the dosage used for suramin (50 mg/kg for Suradista versus 100 mg/kg for suramin). In summary, these results indicate that novel compounds acting like suramin may be developed as effective antineoplastic agents and may also prove to be of clinical benefit.
Finch
P W
PW
Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, N. Y. 10029, USA.
Yee
L K
LK
Chu
M Y
MY
Chen
T M
TM
Lipsky
M H
MH
Maciag
T
T
Friedman
S
S
Epstein
M H
MH
Calabresi
P
P
D016475:3T3 Cells / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002461:Cell Line, Transformed / Q000187:drug effects / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D004247:DNA / Q000096:biosynthesis; D004214:Distamycins / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D013498:Suramin / Q000494:pharmacology; D014162:Transfection; D014471:Umbilical Veins
D000970:Antineoplastic Agents; D016207:Cytokines; D004214:Distamycins; D006131:Growth Inhibitors; D013498:Suramin; D005346:Fibroblast Growth Factors; C030000:stallimycin; D004247:DNA