Tumor tissue is composed of
cancer cells (parenchyma) and
tumor vessels (interstitium). Many investigators have pointed out that blood flow in
tumors has a very inhomogenous distribution, and that this inhomogeneity in blood flow increases as
tumors grew. This would be a certain cause of insufficient drug delivery to
tumor tissues. Among the experimental evidence using
Yoshida Sarcoma and
Ascites Hepatomas, functional differences in microcirculation between
tumor and normal tissues were found by Suzuki et al. (1977). Under hypertensive state induced by the continuous infusion of
angiotensin II,
tumor blood flow increased remarkably, while there was no change or decrease in blood flow in normal tissues such as the brain, bone marrow, liver and kidney. Moreover, the increase in blood flow in
tumors was selective, as the mean blood pressure remained at the level of 150 mmHg. Increases were confirmed not only in many growing sites such as in the liver, muscle, subcutis, and even microfoci, but also in various kinds of xenografted human
tumors and autochthonous
tumors. Augmentation of the anti-
tumor effects of
angiotensin II-induced
hypertension chemotherapy (IHC) for advanced gastric
carcinoma was revealed in two randomized controlled trials (RCT-1 & 2) of collaborative study groups in Japan. The response rates were 42.9% vs 10.5% in RCT-1 and 31.3% vs 6.7% in RCT-2. The frequencies of toxicities were not statistically different. In the results of phase II studies from 1978 to 1994 (OPN-1) and 1995 to 1999 (OPN-2) for advanced gastric
carcinoma (GC), the response rates were 37.9% and 35.7%. Down staging in which the conclusive stage score was lower than the score of the clinical stage, was observed in 8 out of 94 cases (19%) with primary lesions in total and in 30 patients (63%) receiving reduction surgery after IHC, since 1978. It is very important for exact evaluation after
chemotherapy to understand or estimate the pathohistological changes in the
tumor and its degenerated or repaired tissues, which present various clinical images. In the present study, the actual administered dose intensity of
adriamycin (aDIadm) was 5.9 +/- 2.4 mg/sqm/w, and the ratio of aDIadm to the proposed DIadm of reported FAM/FAP schedules was 0.78 +/- 0.32. IHC with smaller DI could lead to a reduction in the accumulation of toxicities of anti-
cancer drugs in the host. In conclusion, IHC might be applied to all kinds of
tumors to enhance the chemotherapeutic effects through selective increase of drug delivery to
tumors.