Antiangiogenic treatment (TNP-470/minocycline) increases tissue levels of anticancer drugs in mice bearing Lewis lung carcinoma.
Although the antiangiogenic agent TNP-470 does not, in general, increase the cytotoxicity of anti-cancer therapies in cell culture, the antiangiogenic agents TNP-470 and minocycline individually and especially in combination have been shown to increase the tumor growth delay produced by several standard cytotoxic therapies in the Lewis lung carcinoma. In an effort to understand the mechanism by which the antiangiogenic agent combination TNP-470/minocycline potentiates the antitumor activity of cytotoxic therapeutic agents in vivo, the biodistribution of [14C]-cyclophosphamide and cis-diamminedichloroplatinum(II) was determined 6 h after cytotoxic drug administration in animals bearing Lewis lung carcinoma pretreated with TNP-470/minocycline and in animals without pretreatment. Higher levels of 14C and platinum were found in 9 tissues (including tumor) except blood in animals pretreated with TNP-470/minocycline. The increased drug levels in the tumors may be sufficient to account for the increased tumor growth delays observed previously. DNA alkaline elution of tumors from animals pretreated with TNP-470/minocycline showed increased DNA cross-linking by both cyclophosphamide and cis-diamminedichloroplatinum(II). The possible implications of these results are discussed.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Dupuis
N P
NP
Robinson
M F
MF
Emi
Y
Y
Goff
D A
DA
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000378:metabolism*; D002330:Carmustine / Q000494:pharmacology; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology; D003510:Cyclohexanes; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004338:Drug Combinations; D008297:Male; D008558:Melphalan / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008911:Minocycline / Q000494:pharmacology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D010984:Platinum / Q000032:analysis; D012717:Sesquiterpenes / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003510:Cyclohexanes; D004273:DNA, Neoplasm; D004338:Drug Combinations; D012717:Sesquiterpenes; D010984:Platinum; D003520:Cyclophosphamide; D008911:Minocycline; D002945:Cisplatin; D008558:Melphalan; D002330:Carmustine; C011272:perfosfamide; D000077609:O-(Chloroacetylcarbamoyl)fumagillol