Potentiation of antitumor activity of irinotecan by chemically modified oligonucleotides

Go-administration of synthetic chemically modified oligonucleotides with ir inotecan, a selective topoisomerase I inhibitor, provided a significant enh ancement in the antitumor activity of irinotecan. The enhancement of antitu mor activity of irinotecan with co-administration of chemically modified ol igonucleotides was observed in several tumor models pancreatic cancer (Panc -1), colon cancer (HCT-116) and melanoma (A375). Inhibition of tumor growth in all three models required the co-administration of irinotecan and chemi cally modified oligonucleotides, but was independent of the nucleotide sequ ence of the oligonucleotides. The potentiation of antitumor activity was de pendent on the dose of irinotecan and chemically modified oligonucleotides administered. The enhancement of antitumor activity of irinotecan was also observed by co-administration of a phosphorothioate oligonucleotide, howeve r, to a lesser extent than did chemically modified oligonucleotides, sugges ting that metabolic stability of the oligonucleotide contributes to the enh ancement of antitumor activity Seen with irinotecan. The co-administration of dextran sulfate sodium with irinotecan showed insignificant potentiation of antitumor activity of irinotecan, suggesting that the enhancement of an titumor activity of irinotecan observed was not a result of polyanionic cha racteristic of oligonucleotides. Coadministration of irinotecan and chemica lly modified oligonucleotides did not result in increased toxicity in the t umor models studied. Potentiation of antirumor activity of irinotecan obser ved with co-administration of oligonucleotides suggests that the oligonucle otides affect the pharmacokinetics and/or metabolism of irinotecan. The use of chemically modified oligonucleotides together with irinotecan may incre ase the therapeutic index of irinotecan in cancer patients and continued de velopment of such agents should be considered.