Tumour necrotisation in nude mice xenografts by the reversible protein synthesis inhibitor zilascorb(2H).
The deuterated benzaldehyde derivative zilascorb(2H), 5,6-O-benzylidene-d-L-ascorbic acid, was administered once daily by i.v. injection in nude mice with grafted tumours of a human malignant melanoma (E.E.) and ovarian carcinoma (OVCAR-3) origins. Like benzaldehyde, zilascorb(2H) has been shown to induce protein synthesis inhibition at otherwise non-toxic doses in cells grown in vitro, and acts reversibly in the sense that protein synthesis returns to normal shortly after removal of the drug. The present data indicate that daily injections with zilascorb(2H) induce a tumour volume growth inhibitory effect in both tumour xenografts studied. Furthermore, from histological examinations of each single tumour it was found that tumours of drug-treated animals, although smaller than those of placebo-treated (i.e. control) animals, had, on average, a higher necrotic fraction than control tumours. Thus, it is concluded that zilascorb(2H) induces tumour necrotisation and not just inhibition of the rate of tumour cell production. Continued measurement of tumour volume after ended treatment with zilascorb(2H) indicated that surviving tumour cells resumed their normal growth rate immediately. The reversibility of the effect induced by this compound, earlier observed in vitro only, is therefore here confirmed to be valid also in two different tumour xenografts in vivo. The present data accords well with the assumption that protein synthesis inhibition is the primary cellular effect of zilascorb(2H) in vivo. We therefore conclude that zilascorb(2H)-induced cancer cell lethality in tumour xenografts probably comes as a secondary consequence of prolonged protein synthesis inhibition.
Pettersen
E O
EO
Department of Tissue Culture, Norwegian Radium Hospital, Oslo.
Larsen
R O
RO
Dornish
J M
JM
Børretzen
B
B
Juul
M E
ME
Aastveit
T E
TE
Nesland
J M
JM
Rofstad
E K
EK
Oftebro
R
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003903:Deuterium; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D009336:Necrosis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D001597:Benzylidene Compounds; D009363:Neoplasm Proteins; D003903:Deuterium; D001205:Ascorbic Acid; C070680:zilascorb