Enhancement of the anti-tumour effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine and bioreductive drugs.
The tumour blood flow inhibitor 5,6-dimethylxanthenone-4-acetic acid (DMXAA) causes dramatic haemorrhagic necrosis in murine tumours, but activity is seen only at doses close to the toxic limit. This study investigates two approaches for increasing the therapeutic ratio of DMXAA. The first approach combines DMXAA with a second tumour blood flow inhibitor, 5-hydroxytryptamine (5-HT). Co-administration of 5-HT (700 micromol kg(-1)) to C3H mice caused marked enhancement of DMXAA effects against MDAH-MCa-4 tumours, with dose-modifying factors (DMFs) of >3 for blood flow inhibition (at 4 h), 2.3 for necrosis (at 12 h) and 2.0 for growth delay, without compromising the maximum tolerated dose of DMXAA (90 micromol kg(-1)). The data are consistent with ischaemic injury to the tumour being the major mechanism of anti-tumour activity. The second approach combines DMXAA (+/- 5-HT) with hypoxia-selective bioreductive drugs. Anti-tumour activity of all three bioreductive drugs tested (tirapazamine, CI-1010, SN 23816) was strongly potentiated by DMXAA, suggesting that there is a population of reversibly hypoxic tumour cells after DMXAA treatment. Co-administration of 5-HT further potentiated anti-tumour activity, but also increased host toxicity of tirapazamine and CI-1010 so that little therapeutic benefit was achieved. In contrast, the host toxicity of the dinitrobenzamide mustard SN 23816 was only slightly increased by DMXAA/5-HT, whereas the tumour growth delay at the maximum tolerated dose of SN 23816 was increased from 3.5 to 26.5 days. This study demonstrates that 5-HT and/or bioreductive drugs can improve the therapeutic activity of DMXAA in mice, and that with SN 23816 both approaches can be used together to provide considerably enhanced anti-tumour activity.
Department of Pathology, The University of Auckland, New Zealand.
C J
CJ
Lash
A E
AE
Li
M
M
Rutland
B C
BC
Baguley
L J
LJ
Zwi
W R
WR
Wilson
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D009593:Nitroimidazoles / Q000008:administration & dosage; D011355:Prodrugs / Q000008:administration & dosage; D012039:Regional Blood Flow / Q000187:drug effects; D012701:Serotonin / Q000008:administration & dosage*; D000077704:Tirapazamine; D014227:Triazines / Q000008:administration & dosage; D014966:Xanthenes / Q000008:administration & dosage*; D044004:Xanthones
C113978:2,4-dinitrobenzamide nitorgen mustard; D000970:Antineoplastic Agents; D009588:Nitrogen Mustard Compounds; D009593:Nitroimidazoles; D011355:Prodrugs; D014227:Triazines; D014966:Xanthenes; D044004:Xanthones; C066668:vadimezan; C067834:RB 6145; D000077704:Tirapazamine; D012701:Serotonin