The antitumour activity of alkylating agents is not correlated with the levels of glutathione, glutathione transferase and O6-alkylguanine-DNA-alkyltransferase of human tumour xenografts. EORTC SPG and PAMM Groups.
Twenty-three human xenografts, including five colon, five gastric, nine lung (three small cell lung cancer) and four breast carcinomas, were investigated for their sensitivity to nitrosoureas, dacarbazine (DTIC), cyclophosphamide (CTX) and cisplatin (DDP). In 12 cases, at least one of the drugs produced complete or partial remission, in 2, a minor regression was observed and in the other 9, treatment was ineffective. The level of sensitivity to each drug, using a score from 1 to 5, was correlated to three biochemical parameters reported to be involved in resistance to alkylating agents: glutathione (GSH), glutathione transferase (GST) and O6-alkylguanine-DNA-alkyltransferase (AGT). A wide variability was found in these parameters in the xenografts investigated. No correlation was found between any of the three parameters and sensitivity to the drugs used or between sensitivity to one drug and to any of the other drugs tested. These results illustrate the complexity of the question of resistance to alkylating agents and indicate that, at least in xenografts, the biochemical parameters examined are not predictive of response to alkylating agents.
D'Incalci
M
M
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Bonfanti
M
M
Pifferi
A
A
Mascellani
E
E
Tagliabue
G
G
Berger
D
D
Fiebig
H H
HH
D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology; D002945:Cisplatin / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D003520:Cyclophosphamide / Q000627:therapeutic use; D003606:Dacarbazine / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism*; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D009607:Nitrosourea Compounds / Q000627:therapeutic use; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D003606:Dacarbazine; D003520:Cyclophosphamide; D019883:Alkyl and Aryl Transferases; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin