ANTITUMOR-ACTIVITY OF A NOVEL PODOPHYLLOTOXIN DERIVATIVE (TOP-53) AGAINST LUNG-CANCER AND LUNG METASTATIC CANCER

We synthesized a potent new antitumor podophyllotoxin derivative (4 -a minoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung meta static cancer. TOP-53 exhibited twice the inhibitory activity of etopo side (VP-16) against topoisomerase II and induced DNA strand breaks bu t showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 mu g/ml and 0.26-8.9 mu g/ml against murine tumor and human non-small ce ll lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted signif icant efficacy equivalent to that of VP-16 on s.c-implanted murine sol id tumors (Colon 26, B16;BL6, and Lewis lung carcinoma) at doses 3-5 t imes lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active fo r two of five tumors. Potent inhibitory activity of TOP-53 was also fo und against a lung tumor (Lewis lung carcinoma) and four lung metastat ic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K17 35M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lu ng cancers but also strongly active against lung localized tumor and m etastatic tumors in the lungs. The high selectivity of TOP-53 was attr ibuted to its high distribution into the lung and its persistence. TOP -53 is expected to be highly effective against lung cancer including N SCLC and various lung metastatic tumors in the clinical field.