The influence of hydralazine on the vasculature, blood perfusion and chemosensitivity of MAC tumours.
We have studied the influence of the peripheral vasodilator hydralazine (HDZ) on the vasculature and blood perfusion of two members of a series of subcutaneous murine adenocarcinomata of the colon (MAC tumours), and the influence of HDZ on the efficacy and/or toxicity of TCNU and melphalan. The fluorescent DNA stain Hoechst 33342, showed that HDZ caused a shutdown of tumour vasculature, related in magnitude to both dose and tumour differentiation state; 10 mg kg-1 caused an 80% vascular shutdown of well differentiated MAC 26 tumours, but only a 50% shutdown of the poorly differentiated MAC 15A tumours. 2.5 mg kg-1 was ineffective. The blood perfusion marker 99mTc-HMPAO showed that the normal perfusion of MAC tumours was consistently markedly less than that of lung, liver or kidneys (4-5% of lung perfusion). HDZ (10 mg kg-1) decreased MAC 26 perfusion by 63%, and that of MAC 15A by 20%. Again, 2.5 mg kg-1) was ineffective. Use of in vivo to in vitro clonogenic assays showed that HDZ (10 mg kg-1) potentiated the efficacy of melphalan (1-10 mg kg-1 i.p.) by a factor of 2.1, and increased the efficacy of TCNU (1-10 mg kg-1 i.v., factor = 1.7) when given 10 or 15 min respectively after dosing. However, the addition of HDZ increased the acute bone marrow toxicity of melphalan, but not that of TCNU. The clinical relevance of these results is discussed.
Quinn
P K
PK
Clinical Oncology Unit, University of Bradford, UK.
Bibby
M C
MC
Cox
J A
JA
Crawford
S M
SM
D000230:Adenocarcinoma / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D000818:Animals; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006830:Hydralazine / Q000494:pharmacology*; D008297:Male; D008558:Melphalan / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008815:Mice, Inbred Strains; D009607:Nitrosourea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011877:Radionuclide Imaging; D012039:Regional Blood Flow / Q000187:drug effects*; D013654:Taurine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014410:Tumor Stem Cell Assay
D009607:Nitrosourea Compounds; D013654:Taurine; D006830:Hydralazine; C052991:1-(2-chloroethyl)-3-(2-(dimethylaminosulfonyl)ethyl)-1-nitrosourea; D008558:Melphalan