A study of the mechanism of hydralazine enhancement of thermal damage in the KHT tumour.
The mechanism of the potentiation of thermal damage by hydralazine (HDZ) has been investigated. Using the KHT sarcoma in the leg of C3H mice, it was shown that 5 mg/kg of HDZ given i.v. 15-20 min before irradiation or heat exposure: (i) increased the radiobiological hypoxic fraction from 1 to 32%; (ii) produced a greater than additive growth delay when combined with heating for 30 min at either 43 or 43.5 degrees C, or 60 min at 43 degrees C; (iii) produced only additive cell killing when combined with 30 min heating at 43, 43.5, or 44 degrees C, assayed by clonogenic cell survival immediately or 24 h after treatment; and (iv) produced a prolonged (greater than 72 h) reduction in relative tissue perfusion (RTP) in the tumour when combined with heating for 30 min at 43.5 degrees C. The effects of HDZ or heat alone lasted for less than 24 and 48 h, respectively. The RTP in skin was unaffected by either agent or combination of agents at the times assayed. The results show that this 30-fold increase in hypoxia does not increase the intrinsic thermosensitivity of KHT tumour cells, and that the prolonged reduction in RTP caused by the combined treatment is probably responsible, at least in part, for the greater than additive component of the measured growth delay in this system. The data suggest that non-perfused tumour vessels are more heat sensitive than perfused vessels.
Honess
D J
DJ
MRC Unit, Cambridge, U.K.
Hu
D E
DE
Bleehen
N M
NM
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D006830:Hydralazine / Q000008:administration & dosage*; D006979:Hyperthermia, Induced; D051379:Mice; D008809:Mice, Inbred C3H; D011836:Radiation Tolerance / Q000187:drug effects; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D014410:Tumor Stem Cell Assay
D006830:Hydralazine