Potentiation of EO9 anti-tumour activity by hydralazine.
EO9[3-hydroxy-5-aziridinyl-1-methyl-2(1H-indole-4,7-dione)prop-bet a-en-alpha-ol] has been selected for phase I evaluation in Europe. Activity has been seen previously in a highly refractory, necrotic mouse adenocarcinoma (MAC 16) but EO9 is shown here to be inactive against early tumours (MAC 15A and MAC 13) and a well vascularised, well-differentiated established adenocarcinoma (MAC 26). EO9 becomes active against MAC 26 tumours when hydralazine (10 mg/kg) is administered 1 min after EO9. Co-administration of hydralazine decreases EO9 plasma clearance and increases plasma area under the curve values (0.053 to 0.115 micrograms h/ml). These pharmacokinetic changes are accompanied by anti-tumour activity but no increase in bone marrow toxicity so this therapeutic gain may be due, at least in part, to microenvironmental changes resulting from hydralazine induced tumour vascular shutdown.
Clinical Oncology Unit, University of Bradford, West Yorkshire, U.K.
M C
MC
Bibby
N R
NR
Sleigh
P M
PM
Loadman
J A
JA
Double
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D001388:Aziridines / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D001853:Bone Marrow / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006207:Half-Life; D006830:Hydralazine / Q000627:therapeutic use; D045563:Indolequinones; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D051379:Mice
D000970:Antineoplastic Agents; D001388:Aziridines; D045563:Indolequinones; D007211:Indoles; D006830:Hydralazine; C060817:apaziquone