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In previous studies we found degradable starch microspheres (DSM) to increase the antitumor effect of adriamycin injected by the hepatic artery in rats with a liver adenocarcinoma. Increased side effects also appeared, namely body weight loss and liver necroses. In the present paper, norepinephrine in four different protocols was added to the injection of adriamycin + DSM to decrease the drug flow to normal tissues. In two protocols norepinephrine decreased the body weight loss. There was also a non-significant decrease in liver necroses but also in antitumor effect. In these experiments we also observed that some rats given adriamycin + DSM got gastric necroses. This was not found when norepinephrine was added. Addition of propranolol to norepinephrine did not decrease side effects. Vasoactive drugs may therefore be of value to diminish adverse side effects of the combination cytostatic agent + DSM, probably decreasing overspill into normal tissues.

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.

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.

One of the main cytotoxic effects of 5-FU is its incorporation into RNA. In rats, protein deprivation increases the incorporation of labelled precursors into liver RNA. We examined the effect of protein deprivation on the incorporation of a therapeutic dose of 5-FU into the liver, small intestine, kidney and bone marrow and into an adenocarcinoma transplanted to the liver in the rat. The rats were fed either on a 25% or a 0% casein diet for one week. Some rats from both groups were given amino acids or glucose parenterally. Therapeutic 5-[3H]-FU was given in a 2 h infusion by the hepatic artery and the rats were sacrificed one h later. Incorporation into liver and intestinal RNA increased significantly with protein deprivation. The increase was largely eliminated by parenteral feeding of amino acids. No differences were found in incorporation into tumor and bone marrow RNA in protein deprivation. Incorporation into the acid soluble fraction and DNA is also reported.

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.