zinostatin and Hypertension

The purpose of this study is to evaluate the improved method of arterial infusion therapy of SMANCS (SX) with lipiodol under the angiotensin-induced hypertensive state for various difficult-to-treat solid tumors. Most patients were unresectable with no other therapeutic options, recurrence after resection, or patients do not respond to common treatments. The new method utilizes angiotensin II (AT) to induce hypertension (e.g. approximately 15-30 mmHg above norm) for 15-20 min. This method was successfully applied to metastatic liver cancer, cholangiocarcinoma, massive renal cell carcinoma, pancreatic and other abdominal solid cancers. This AT-induced hypertension resulted in remarkably enhanced tumor delivery accompanied by improved therapeutic response, and a shorter time to achieve 50% regression of tumor size with least toxicity. We demonstrated clinically herein improved therapy for various advanced solid tumors with SX by elevating the tumor blood flow selectively. This is the first clinical proof that modulations of vascular pathophysiology can uniquely accomplish enhanced tumor selective delivery of polymeric drugs and thus yielded better clinical outcome.

Topics: Adenocarcinoma; Adult; Aged; Angiotensin II; Antineoplastic Agents; Blood Pressure; Carcinoma, Renal Cell; Cholangiocarcinoma; Drug Delivery Systems; Female; Humans; Hypertension; Infusions, Intravenous; Japan; Kidney Neoplasms; Liver Neoplasms; Male; Maleic Anhydrides; Middle Aged; Neoplasm Staging; Neoplasms; Ovarian Neoplasms; Pancreatic Neoplasms; Polystyrenes; Vasoconstrictor Agents; Zinostatin

Effects of angiotensin II (AT-II)-induced hypertension on the distribution of macromolecules to Walker carcinoma and to bone marrow of SMANCS [poly(styrene-co-maleic-acid)-neocarzinostatin conjugate] were investigated in rats. AT-II-induced hypertension from about 100 to 150 mmHg significantly increased the accumulation of the macromolecular drug SMANCS and 51Cr-labelled bovine serum albumin ([51Cr]BSA), representatives of macromolecular drugs, in tumour tissue. At 1 h after i.v. administration, intratumour concentrations of [51Cr]BSA and SMANCS were elevated by 1.2-1.8-fold. The higher drug accumulation in the tumour that was produced by the artificial hypertension was retained even 6 h after administration. This observation indicates an additive effect to that under normotensive conditions where intratumour macromolecular drug concentrations increase steadily during this period. Furthermore, distributions of these drugs in the bone marrow and the small intestine decreased during artificial hypertension to 60-80% of those in the normotensive state. Therefore, the drug concentration ratios of tumour/bone marrow and tumour/small intestine were increased by 1.8-2.4-fold. A decreased distribution of SMANCS to normal tissues under hypertensive conditions was also confirmed by the significant reduction of its toxicity e.g. leukopenia, diarrhoea, and body weight loss, even at a lethal dose. On the contrary, [3H]methylglucose showed no remarkable difference in tumour or bone marrow accumulation under this hypertensive condition. These results show the advantages of macromolecules over small molecules for AT-II-induced hypertension chemotherapy.

Topics: Angiotensin II; Animals; Blood Pressure; Bone Marrow; Capillary Permeability; Carcinoma 256, Walker; Female; Hypertension; Maleic Anhydrides; Methylglucosides; Polystyrenes; Rats; Rats, Wistar; Serum Albumin, Bovine; Tissue Distribution; Zinostatin

On the basis of the observation that the tumor tissue blood flow selectively increases under angiotensin (AT)-induced hypertension, the change of the drug concentration in the tumor and normal tissues was examined in male Donryu rats. The intratumor concentration of fluorescein isothiocyanate-labeled neocarzinostatin was about 2-fold higher in the AT-induced hypertension group than in the control up to 20 min after the drug injection. In the normal organs or the uninvolved organs of the tumor-bearing rats, however, no clear increase was seen in the experimental group compared with the control, as anticipated from the observation of the tissue blood flow. The present study supports the hypothesis that the enhanced anticancer effect in chemotherapy under AT-induced hypertension formerly reported is due to the tumor-selective enhancement of the drug delivery.

Topics: Angiotensin II; Animals; Antibiotics, Antineoplastic; Biological Transport; Fluorescein-5-isothiocyanate; Fluoresceins; Hypertension; Neoplasms, Experimental; Rats; Thiocyanates; Zinostatin