Antitumor activity of S 16020-2 in two orthotopic models of lung cancer.
S 16020-2, a new olivacine derivative selected on the basis of its cytotoxicity in vitro and antitumor activity in vivo, was evaluated against the human A549 and the murine Lewis lung tumor models implanted s.c. and i.v. Against Lewis lung carcinoma implanted s.c., S 16020-2 was found to be curative, with an activity and therapeutic index (Ti = 4) similar to that of cyclophosphamide. S 16020-2 administered weekly demonstrated a high therapeutic efficacy against A549 non-small cell lung carcinoma implanted s.c. in nude mice and induced tumor regression at 80 mg/kg. When A549 tumor cells were injected i.v. in SCID mice, experimental metastases rapidly developed and the progressive invasion of the lung tissue by tumor preceded the death of animals. In this model, S 16020-2 administered at 40 mg/kg i.v. following an early (days 8, 18 and 28) or delayed (days 20, 30 and 40) treatment schedule prolonged the survival of tumor-bearing mice with T/C values of 150 and 145%, respectively. Against the i.v. Lewis lung carcinoma, S 16020-2 was also highly active since when administered at 60 mg/kg on days 5, 9 and 13 it totally inhibited tumor growth and cured up to 89% of mice. When administered on days 11, 15 and 19 to animals with established tumors, S 16020-2 was still active but not curative. In the presented studies, S 16020-2 antitumor activity was superior to that of adriamycin and comparable or superior to cyclophosphamide (used as reference compounds). Our results demonstrate the efficacy of S 16020-2 against these highly aggressive and chemoresistant tumor models.
Guilbaud
N
N
Institut de Recherches Servier, Division de Cancérologie Expérimentale, Suresnes, France.
Kraus-Berthier
L
L
Saint-Dizier
D
D
Rouillon
M H
MH
Jan
M
M
Burbridge
M
M
Pierré
A
A
Atassi
G
G
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy* / Q000473:pathology; D003520:Cyclophosphamide / Q000627:therapeutic use; D004611:Ellipticines / Q000627:therapeutic use*; D006801:Humans; D008136:Longevity / Q000187:drug effects; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D013534:Survival; D014183:Transplantation, Heterologous
D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D004611:Ellipticines; C101591:S 16020-2; D003520:Cyclophosphamide