ANTITUMOR-ACTIVITY OF A C-RAF ANTISENSE OLIGONUCLEOTIDE IN COMBINATION WITH STANDARD CHEMOTHERAPEUTIC-AGENTS AGAINST VARIOUS HUMAN TUMORS TRANSPLANTED SUBCUTANEOUSLY INTO NUDE-MICE

A 20-mer phosphorothioate oligodeoxynucleotide (ODN) directed against human C-raf kinase (CGP 69846A or ISIS 5132) was analyzed for its anti tumor activity either alone or in combination therapy. Combination stu dies with CGP 69846A and standard chemotherapeutic agents (cisplatin, mitomycin C, tamoxifen, or Adriamycin) were performed in nude mice tha t had been transplanted s.c. with a variety of human tumors (breast, p rostate, colon, small cell lung, large cell lung, and squamous lung ca rcinomas). For the majority of the combinations studied, additive anti tumor effects with CGP 69846A and the cytotoxins were found. The combi nation of CGP 69846A with cisplatin or mitomycin C showed superadditiv e antitumor activities against NCI-H69 small cell lung carcinomas with complete tumor responses, CGP 69846A, in combination with cisplatin, showed superadditive antitumor effects against PC3 human prostate carc inomas with tumor cures, and in combination with mitomycin C, superadd itive antitumor effects of CGP 69846A with tumor cures against NCI-H46 0 large cell lung carcinoma were found. These effects appeared to be s equence-specific because a mismatched control ODN was completely witho ut effect as a single agent against NCI-H69 human small cell lung canc ers. The combination of the mismatched control ODN with mitomycin C or cisplatin did not influence the antitumor activity of the cytotoxins against NCI-H69 human small cell lung cancers, indicating that the sup eradditive antitumor effects observed for CGP 69836A in combination wi th cisplatin or mitomycin C are the result of a sequence-specific mech anism of action in NCI-H69 human small cell lung cancers.