Decreased binding sites of angiotensin II in rat LY-80 and AH109A tumour and human gastric cancer using quantitative in vitro autoradiography.
BACKGROUND
Under systemic hypertension induced by angiotensin II (AII) infusion, an attenuated vasoconstrictive response to the infusion in tumours was observed and a marked increase in tumour blood flow was observed in comparison with that in normal tissues. The results show a parallel circuit that connects the vascular bed of the pre-existing tissue to that of the tumour. The phenomenon was absent when hypertension was provoked by other vasoconstrictive agents such as norepinephrine or endothelin-1. However, the biological basis for this attenuated vasoconstrictive response to angiotensin II observed in tumours has not been fully elucidated.


METHODS
We assessed this response to characterise the angiotensin II receptor density and affinity in normal and tumour tissues. AH109A and LY80 tumour cell lines were transplanted to the skin in nude rats. Four weeks later, the rats were sacrificed. 125I-[Sar1, Ile8] angiotensin II was used to map its receptors in rat tissues using in vitro computerised autoradiography. Operated human gastric cancer tissues from a 49-year-old and a 66-year-old male patients were also investigated.


RESULTS
The numbers of angiotensin II receptors were markedly reduced in tumour tissues without a change of affinity. The numbers in AII-R in tumours were shown to be mainly AT1 by the marked reduction in radioligand binding achieved by losartan but not by PD123177. The same results were observed in human gastric cancer.


CONCLUSIONS
These results suggest that the decrease in angiotensin II receptors in tumours may explain the haemodynamic effect of angiotensin II-induced hypertension on tumour blood flow. This condition for drug delivery to tumour tissue may play a major role in enhancing the therapeutic effects of chemotherapy.
Kohzuki
M
M
Section of Internal Medicine & Disability Prevention, Tohoku University Graduate School of Medicine, Sendai, Japan. kohzuki@mail.cc.tohoku.ac.jp
Tanda
S
S
Hori
K
K
Suzuki
M
M
Yoshida
K
K
Sato
T
T
D000368:Aged; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001345:Autoradiography; D001665:Binding Sites; D014408:Biomarkers, Tumor; D001783:Blood Flow Velocity; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011923:Rats, Nude; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured
D047228:Angiotensin II Type 1 Receptor Blockers; D057912:Angiotensin II Type 2 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D014408:Biomarkers, Tumor; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000804:Angiotensin II; C066253:PD 123177; D019808:Losartan