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The degradable starch microspheres (DSM) used have a size of 45 microns and are dissolved by amylase in blood. After intraarterial administration of a mixture of DSM and cytostatic drugs the coinjected drugs remain for a longer time in the target tissue/tumor. A transient hypoxia occurs. Systemic exposure of drugs is decreased. Rats with a carcinoma implanted into the liver were given DSM and drugs via the hepatic artery. DSM did not significantly increase the incorporation of 5-fluorouracil (5-FU) into liver tumor RNA. The incorporation of 5-FU into intestinal and bone marrow RNA increased. DSM increased the antitumor effect of doxorubicin, tauromustine, carmustine and RSU-1069 (aziridine 2-nitroimidazole). Side effects, such as liver and gastric necroses and body weight loss, appeared in some rats. The toxic overspill to the stomach seemed to be reduced by giving the DSM in two parts, with all the cytotoxic drug in the first part. The effect on liver and tumor was not decreased by this procedure. DSM alone had no anti-tumor effect. DSM alone decreased liver UDP-glucuronic acid in tumor-free rats, given either by the hepatic artery or, in the double dose, by the portal vein. DSM alone did not increase liver NADPH-cytochrome c reductase activity or serum ASAT (aspartate-aminotransferase) or ALAT (alanine-aminotransferase), indicating that the DSM are inert to the liver, when infused into the tributary vessels.

Rats with an adenocarcinoma of the colon implanted into the liver were treated by a bolus injection of adriamycin by the hepatic artery. In addition, vascular occlusions were performed in the following three ways. 1. The hepatic artery was ligated (HAL) immediately after adriamycin injection. 2. The portal venous branch nourishing the tumor was ligated immediately after adriamycin injection. 3. The Pringle maneuvre (clamping of the hepatic artery, the portal vein and the common bile duct) was performed during 5 min before and 10 min after injection. Tumor size was measured at operation and 6 and 12 days later in the first experiment, 7 days later in the other two experiments. The combination of adriamycin and HAL retarded tumor growth at day 6 as compared to controls, adriamycin alone and HAL alone. The differences were not significant at day 12. The other vascular occlusions did not improve the antitumor effect of adriamycin.

A therapeutic dose of labelled 5-fluorouracil (5-FU) was infused via the hepatic artery during 30 min with or without a simultaneous temporary clamping of the portal vein in a model of secondary liver cancer in Wistar rats. After another 60 min, the incorporation of 5-FU into the acid soluble fraction, RNA and DNA was determined in tumor, liver, small intestine, kidney, and bone marrow. The liver and intestinal nucleotide profiles were examined with isotachophoresis. Temporary portal vein clamping caused the following changes, as compared with the control group with intraarterial infusion only: in the liver, the incorporation of 5-FU into the acid soluble fraction increased without a concomitant increase into the RNA or of the level of (F)UTP. Liver ATP decreased. In the tumor, the ratio of RNA to acid soluble fraction labelling decreased. There was a generally decreased ratio of tumor to peripheral normal tissue (small intestine and kidney) labelling. In conclusion, portal vein clamping in conjunction with hepatic arterial administration of 5-FU led to a decreased anabolism of 5-FU in the liver and tumor, and increased systemic drug exposure. It is not known how this interferes with the therapeutic effect.

The cytotoxicity of 5-FU and 5-FUrd, given via the hepatic artery, was measured by its incorpotation into the acid soluble fraction, RNA and DNA in normal tissues and an adenocarcinoma transplanted into the liver in rats. Drugs inhibiting the membrane transport of, especially, nucleosides were simultaneously administered by a femoral vein to modulate the cytotoxicity. None of them (dipyridamole, lidoflazine nor dilazep) had any statistically significant influence on the tumour. Dipyridamole and lidoflazine decreased the incorporation of 5-FU into the acid soluble fraction, RNA and DNA of the intestine. Dipyridamole probably decreased the incorporation of 5-FUrd into the acid soluble fraction and RNA of the intestine. Lidoflazine has not been tested with 5-FUrd. Dipyridamole increased the incorporation of 5-FU into the acid soluble fraction of liver, bone marrow and kidney, and of 5-FUrd into the acid soluble fraction of liver and bone marrow and liver RNA. Lidoflazine had fewer adverse effects. Both dipyridamole and lidoflazine increased the combined peak of UTP and FUTP in the liver, and dipyridamole also in the intestine of 5-FU treated rats. Dipyridamole which undergoes an enterohepatic circulation increased the combined peak of UDP-glucuronic acid and FUDP-glucuronic acid in 5-FU and 5-FUrd treated rats, as well as UDP-glucuronic acid in rats given neither 5-FU nor 5-FUrd in the liver. Membrane transport inhibitors seem to offer the opportunity to protect normal tissues from the cytotoxicity of 5-fluoropyrimidines, but the tissues can also be more exposed.

The cytotoxicity of 5-FU, given by the hepatic artery, was measured by its incorporation into the acid soluble fraction, RNA and DNA in normal tissues and an adenocarcinoma transplanted into the liver in rats. Other substances were simultaneously administered by the portal vein to modulate the cytotoxicity. None of them had any significant influence on the incorporation of 5-FU into tumor. Dipyridamole decreased the incorporation of 5-FU into liver RNA and increased the nucleotide/DNA and RNA/DNA ratios so that the incorporation into mg RNA per liver cell was unchanged. Dipyridamole decreased the incorporation into the acid soluble fraction, RNA and DNA of the small intestine and also into RNA per mg DNA. It increased the nucleotide/RNA and RNA/DNA ratios in the bone marrow. Orotate decreased the incorporation into liver and intestinal RNA. Uridine increased the incorporation into liver RNA. The results obtained with dipyridamole were the most pronounced. Studies are continuing with this and other membrane transport inhibitors.

Cytostatic treatment of liver metastases from colorectal cancer has been of limited value. Higher drug levels in the target substances of the tumor may improve the results. It was the aim of this investigation to examine the effect of PALA (N-phosphonacetyl-L-aspartate) and D-glucosamine on the level of uracil nucleotides in the liver and in an N-methyl-N-nitrosoguanidine-induced adenocarcinoma of the colon transplanted to the liver of rats, and on the incorporation of 3H-FUrd into the acid-soluble fraction, the RNA and the DNA of the tumor and of several normal tissues. Combined treatment with PALA and D-glucosamine reduced the UTP pool in the liver and the tumor. D-glucosamine alone increased UDP-N-acetyl-hexosamine in liver tissue. Pretreatment with PALA and D-glucosamine increased incorporation of 3H-FUrd into RNA of the liver and kidney, and into the DNA fraction of the liver, but had no effect on 3H-FUrd incorporation in the tumor.