Antitumor activity of a new low immunosuppressive derivative of podophyllotoxin (GP-11) and its mechanisms.
The spin-labeled derivative of podophyllotoxin, N'-podophyllic acid-N-[3-(2,2,5,5-tetramethyl pyrrolinenyloxy)] semicarbazide (GP-11), was synthesized and tested for its antitumor activity against mouse transplantable tumors, Sarcoma-180, Hepatoma-A, P388 leukemia and Ehrlich ascites carcinoma. At an equitoxic dose, the antitumor activity of GP-11 was similar to that of etoposide (VP-16). However, the immunosuppressive effects of GP-11 were weaker than that of VP-16. In vitro, GP-11 and VP-16 inhibited the proliferation of human lymphoid leukemia Molt 4B cells and suppressed DNA and protein syntheses, but the effect of GP-11 and VP-16 on cell cycle progression was different. The mitotic index was increased by GP-11 and reduced by VP-16. On the basis of flow cytometric bromodeoxyuridine (BrdU)/DNA analysis, GP-11 and VP-16 resulted in the accumulation of cells in the S and G2/M phases. G2/M arrest by GP-11 on cell cycle progression was stronger than that of VP-16, while S arrest was weaker than that of VP-16. After the removal of drugs, the arrest by GP-11 and VP-16 still existed and was irreversible. These results may provide insights into the structure-activity relationships and the design of novel derivatives of podophyllotoxin useful in cancer chemotherapy.
Wang
J Z
JZ
Department of Pharmacology, Mie University School of Medicine, Japan.
Tian
X
X
Tsumura
H
H
Shimura
K
K
Ito
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000737:chemistry / Q000494:pharmacology*; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis; D066298:In Vitro Techniques; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D011033:Podophyllin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D011034:Podophyllotoxin / Q000031:analogs & derivatives*; D013113:Spin Labels; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D007166:Immunosuppressive Agents; D013113:Spin Labels; D005047:Etoposide; C081861:GP 11; D011033:Podophyllin; D011034:Podophyllotoxin