Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo.
BACKGROUND
Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties.


METHODS
The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorubicin according to the optimal dose and schedule for each drug. The drug's cytotoxic effects, induction of DNA damage, and intracellular accumulation were studied in A2780 cells. DNA cleavage mediated by the enzyme topoisomerase II was investigated in vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug concentrations and analyzing the DNA cleavage-intensity patterns. Drug-induced apoptosis (programmed cell death) in tumors was determined with the use of MX-1 and POVD tumor-bearing athymic Swiss nude mice.


RESULTS
MEN 10755 was more effective than doxorubicin as a topoisomerase II poison and stimulated DNA fragmentation at lower intracellular concentrations. In addition, MEN 10755 exhibited striking antitumor activity in the treatment of human tumor xenografts, including those of the doxorubicin-resistant breast carcinoma cell line MX-1.


CONCLUSIONS
The high antitumor activity of MEN 10755 in human tumor xenografts, including doxorubicin-resistant xenografts, and its unique pharmacologic and biologic properties make this disaccharide analogue a promising candidate for clinical evaluation.
Arcamone
F
F
Menarini Ricerche, Rome, Italy.
Animati
F
F
Berettoni
M
M
Bigioni
M
M
Capranico
G
G
Casazza
A M
AM
Caserini
C
C
Cipollone
A
A
De Cesare
M
M
Franciotti
M
M
Lombardi
P
P
Madami
A
A
Manzini
S
S
Monteagudo
E
E
Polizzi
D
D
Pratesi
G
G
Righetti
S C
SC
Salvatore
C
C
Supino
R
R
Zunino
F
F
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D018288:Carcinoma, Small Cell / Q000188:drug therapy; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000187:drug effects*; D004187:Disaccharides / Q000138:chemical synthesis; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy; D013997:Time Factors; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004187:Disaccharides; D004317:Doxorubicin; D004250:DNA Topoisomerases, Type II; C107602:sabarubicin