Antitumour effect of combination treatment with Sabarubicin (MEN 10755) and cis-platin (DDP) in human lung tumour xenograft.
OBJECTIVE
Sabarubicin (MEN 10755), a new disaccaride anthracycline, has shown greater efficacy than Doxorubicin in a large panel of preclinical models and now it is in phase II clinical trials. Its promising antitumour activity promoted considerable interest to combine Sabarubicin with other antitumour agents. Thus, the purpose of this study was to evaluate in vitro cytotoxic effects and in vivo antitumour activities produced by the combination of Sabarubicin and cisplatin (DDP).


METHODS
The antitumour effect of Sabarubicin and DDP association was investigated, in vitro and in vivo, in preclinical models of lung cancer i.e.: the non-small cell lung carcinoma (NSCLC) H460 and the small-cell lung carcinoma (SCLC) GLC4 in terms of synergism, additivity or antagonism in order to establish the best schedule for the combined treatment. Further, the correlation between antitumour activity and the pharmacokinetic parameters of the studied combination was also evaluated.


RESULTS
The drug combination in vitro was in general more cytotoxic than the single drug alone, indicating the presence of a synergistic effect in both tumour cell lines. Also, in the xenograft experiments a superior antitumoral effect was observed when Sabarubicin was combined with DDP. The antitumour efficacy of Sabarubicin (6 mg/kg q4d x 5) combined with DDP (6 mg/kg q4d x 3) greatly depended on the schedule of administration. In H460 tumour line, the sequential combination was more effective than the simultaneous administration of the two agents, although the antitumour efficacy was not dependent on the sequence of combination. On the other hand, a strong sequence-dependent effect was observed when Sabarubicin was combined with DDP in SCLC, GLC4. In particular, the highest value of LCK = 6.7 was obtained when administration of DDP followed by 24 h that of Sabarubicin. Pharmacokinetics of Sabarubicin in combination with DDP was evaluated at 6 mg/kg for both drugs with different sequential schedule. The experimental data showed no evidence for pharmacokinetics drug-drug interaction.


CONCLUSIONS
These preclinical results indicate the potential for a strong antitumour activity in lung tumours of the combination Sabarubicin and DDP. In particular, in SCLC the best response should be given by a sequence with administration of Sabarubicin followed 24 h later by that of DDP. Clinical trials based on these results are ongoing.
Department of Pharmacology and Pharmacokinetics, Menarini Ricerche S.p.A, Via Tito Speri 10, 00040, Rome, Pomezia, Italy. mbigioni@menarini-ricerche.it
M
M
Bigioni
A
A
Benzo
C
C
Irrissuto
G
G
Lopez
B
B
Curatella
C A
CA
Maggi
S
S
Manzini
A
A
Crea
S
S
Caroli
F
F
Cubadda
M
M
Binaschi
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004187:Disaccharides / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014183:Transplantation, Heterologous; D023041:Xenograft Model Antitumor Assays
D004187:Disaccharides; D004338:Drug Combinations; D004317:Doxorubicin; D002945:Cisplatin; C107602:sabarubicin