Can preoperative psychological defensive strategies, mood and type of lower urinary tract reconstruction predict psychosocial adjustment after cystectomy in patients with bladder cancer?

OBJECTIVES: To assess if there is relationship between: (i) preoperative psychological defensive strategies, mood and type of lower urinary tract reconstruction, and (ii) psychosocial adaptation after radical cystectomy for bladder cancer. PATIENTS AND METHODS: Fifty-seven consecutive patients (44 men and 13 women, mean age 62 years, range 34-81) undergoing radical cystectomy (ileal conduit urinary diversion in 17, continent cutaneous diversion in 22 and orthotopic bladder replacement in 18) were assessed preoperatively using the meta-contrast technique (MCT), a projective test to reveal individual defensive strategies. From the results the patients were classified as hypothetical 'at risk' or 'no risk' patients for postoperative psychosocial complications. An 'at risk' patient was designated as one who showed neurotic defensive strategies in coping with threats, i.e. primitive, immature or regressive strategies or even lack of defence in connection with pronounced anxiety. All patients completed a questionnaire and were interviewed; 10 questions dealt with mood, five reflecting anxiety and five the depressive states. The questionnaire and the interview were repeated 3 and 12 months, and 5 years after surgery. RESULTS: The remembered difficulties during the first month after discharge from hospital differed between the 'risk' and 'no risk' groups after 1 and 5 years. On a visual analogue scale (VAS) the 'risk' patients had very low scores (less difficulty) or very high, while the 'no risk' patients had intermediate scores. VAS score were also higher, although not significantly so, in patients using primitive defence strategies. The psychosocial situation did not differ between the groups in the first year, but at 5 years there were differences in self-esteem and interpersonal contact-seeking. High depression scores before surgery were associated with high VAS scores at 3 months when recalling the first month after discharge, but the anxiety score was not predictive. Men with orthotopic bladder replacement adapted less well throughout the 5 year follow-up. Elderly patients with stereotypy (the commonest defensive strategy at these ages) adapted relatively well to ileal conduit diversion. About 20% of patients had difficulty in accepting the postoperative situation, regardless of urinary diversion modes. CONCLUSION: The combination of defensive strategies assessed using the MCT and selected on hypothetical grounds was less discriminatory than expected for those at risk of postoperative psychosocial problems. However, those with primitive strategies apparently had a long-term risk of poor adaptation. The search for an optimal instrument for the identification of patients at risk is warranted. In this study, patients with a 'wet' stoma did not seem to fare less well than those with a continent reconstruction.

Effect of drug scheduling on the antitumor-activity and bone-marrow toxicity of tauromustine (tcnu).

The effect of administering divided dose schedules of TCNU was examined against the murine adenocarcinomas of the colon, MAC 13 and MAC 26, and the Lewis lung tumour and drug metabolism was examined in the different tumour bearing mouse strains. Bone marrow toxicity of the dose schedules was assessed using a spleen colony forming unit assay. In addition, the effect of drug scheduling was investigated in a Phase I clinical setting. Differing levels of efficacy of the divided dose schedules were observed in the different murine tumour models. A therapeutic advantage was found in the Lewis lung tumour whereas none was found in either MAC 13 or MAC 26 tumours. The extent and nature of TCNU metabolism varied between the mouse strains which might contribute to the differing activity-toxicity patterns obtained. The results suggest that divided dose scheduling of TCNU might only be useful in selected patients.

Degradable starch microspheres in cytostatic treatment of a liver carcinoma; experimental studies in rats with 5-fluorouracil, tauromustine, carmustine, doxorubicin and RSU-1069.

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.

The antitumor effects of the quinoline-3-carboxamide linomide on Dunning R-3327 rat prostatic cancers.

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3- carboxamide) is a quinoline 3-carboxamide which previously has been demonstrated to produce immunomodulator and antitumor effects when given in vivo. To test the possible antitumor effects of linomide against prostatic cancers, rats bearing five distinct Dunning R-3327 rat prostatic cancer sublines were treated daily with i.p. injections of linomide. These studies demonstrated that linomide has a reproducible antitumor effect against all of the prostatic cancers tested regardless of their growth rate, degree of morphologic differentiation, metastatic ability, or androgen responsiveness. This antitumor effect is observed only in vivo, not in vitro, and involves a cytotoxic response of the prostatic cancer cells. This cytotoxic response results in the retardation of the growth rate (i.e., increased tumor volume doubling time) of primary prostatic cancers and in metastatic lesions. Linomide's growth retardation is reversible, and thus continuous daily treatment with linomide is required for maximal antitumor response. Pretreatment of rats with linomide before tumor inoculation has no effect in addition to that produced by initiating linomide treatment at the time of tumor inoculation. No enhancement of either natural killer cell number or natural killer cell cytotoxic activity is induced by linomide treatment in the tumor-bearing rats. In addition, depletion of natural killer cell activity via injections of asialo-GM1 antiserum does not prevent the antitumor effects of linomide in vivo. Likewise, the antitumor effects of linomide are also produced in prostatic cancer-bearing athymic nude rats. These results suggest that the requirement for host involvement in the antitumor effects of linomide against rat prostatic cancers may involve both immune and nonimmune host mechanism(s) (e.g., antiangiogenesis).

The antitumor effect of a novel nitrosourea, tauromustine, at intravenous administration in rat. Cure of hepatomas.

The effect of intravenously injected tauromustine (TCNU) on tumor growth and body weight was studied in rats with subcutaneously implanted experimental carcinomas. With a colonic tumor, a single dose or that dose split on 4 consecutive days gave the same tumor growth delay but the body weight loss was less at the split dose. Injection of the single dose for 1 min, 30 min or 2 h each had the same effect. Rats of another strain were implanted with a hepatoma. 9 out of 10 rats were cured. A late effect was body weight loss due to disturbed growth of the teeth.

Nucleic acid labeling with [3H]orotic acid and nucleotide profile in rats in protein deprivation, enteral and parenteral essential amino acid administration, and 5-fluorouracil treatment.

Rats were fed a 0% casein diet for 1 week, with or without enteral or parenteral administration of essential amino acids, or a 25% casein diet, in one group supplemented with 5-fluorouracil treatment. Ninety minutes before sacrifice the rats were given a tracer of [3H]orotic acid. Incorporation into the acid soluble fraction, RNA, and DNA was determined in liver, small intestine, bone marrow, and kidney. Nucleotide profile was examined in liver and intestine. Protein deficiency caused inter alia a decrease in body weight; a decrease in RNA/DNA ratio and an increase in the specific RNA labeling in liver and kidney; an altered nucleotide profile in the liver; an increase in the nucleotide/DNA and RNA/DNA ratios and a decrease in the specific labeling of the acid soluble fraction, RNA, and DNA in the bone marrow. These changes were prevented to the same extent by giving essential amino acids, either orally or intravenously. The minor changes in intestinal nucleotide profile in protein deprivation were prevented to a slightly larger extent by amino acids orally than parenterally. 5-Fluorouracil treatment gave a decrease in the RNA/DNA ratio in the liver and kidney but an increase in the nucleotide/DNA and RNA/DNA ratios in the bone marrow. Nucleotide profiles were unaltered. The amount of DNA per gram of tissue decreased in bone marrow and increased in kidney. Parenteral administration per se resulted in almost no changes.

Enhanced effect of adriamycin on a rat liver adenocarcinoma after hepatic artery injection with degradable starch microspheres.

Rats with solitary liver tumors were treated with adriamycin administered via the hepatic artery with and without degradable starch microspheres. Tumor growth inhibition was significantly greater, and tumors were decreased in size 7 days after, following treatment with adriamycin + microspheres. The bone marrow seemed to be protected. However, the addition of microspheres to adriamycin gave a body weight loss and evidence of increased liver damage. Possible interrelations between liver damage, antitumor effect and body weight loss are indicated.

Characterization of muscarinic cholinergic receptors in membrane preparations from rat prostatic adenocarcinoma.

The binding characteristics of 3H-quinuclidinyl benzilate (QNB) to muscarinic sites in isolated plasma membrane fractions from R-3327 Dunning tumors (H and AT-1 sublines); ventral, dorsolateral prostate; and urinary bladder of the rat were studied. QNB binding to all preparations, except from AT-1 tumors, was specific, saturable, and of high affinity. The AT-1 tumors completely lacked specific QNB binding. The muscarinic receptor density in H tumors was twofold and twentyfold higher than that in the ventral prostate and dorsolateral prostate respectively. The receptor density in the urinary bladder was approximately twofold higher than that in H tumors. The Kd values in H tumors and ventral prostate were very similar and significantly higher than that in dorsolateral prostate or the urinary bladder. QNB binding in H tumors was strongly inhibited by classical muscarinic receptor antagonists atropine and scopolamine, but poorly by the agonists carbacholine and pilocarpine. In contrast to scopolamine or atropine, inhibition by pirenzepine and AF-DX116 was relatively low. These data indicate that the muscarinic receptor in Dunning H tumors is of M3 type.

Modulation of 5-fluorouracil and 5-fluorouridine toxicity by membrane transport inhibitors in normal tissues of rats with liver adenocarcinoma.

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.

Effects of dosage and infusion time on the incorporation of 5-fluorouracil into DNA and RNA of normal tissues and an adenocarcinoma transplanted to rat liver.

In a model of secondary liver cancer in Wistar rats the incorporation of 5-FUra into the acid soluble fraction, RNA, and DNA of several normal tissues and of an adenocarcinoma of the colon transplanted to the liver was determined; 300, 1,200 or 24,000 nmoles of 5-FUra were infused via the gastroduodenal artery for 0.5, 2, or 24 hr. The rats were killed 1.5, 3, or 24 hr after the beginning of the infusions. In general, higher doses resulted in a higher labelling. However, the ratio of incorporation into tumor RNA compared to normal tissue RNA was higher at the 1,200 than at the 24,000 nmole dosage. There was a decreased RNA/DNA ratio in the tumor at 24 hr after 24,000 nmoles of 5-FUra had been infused over 0.5 or 2 hr, indicating decreased synthesis and/or increased breakdown of RNA.

Anti-tumour, toxicological and pharmacokinetic properties of a novel taurine-based nitrosourea (TCNU).

A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulfonyl) ethyl]-1-nitrosourea (TCNU) tauromustine, has been investigated in a broad anti-tumour screen and, in depth toxicology and initial pharmacokinetics carried out. TCNU and its two metabolites were found to exhibit equal or better oral efficacy than that of BCNU, CCNU, MeCCNU or chorozotocin against L1210 leukemia, Walker mammary carcinoma, Lewis Lung, Harding Passey melanoma and colon carcinoma C26. The toxicological profile of TCNU after acute and 3 months treatment was similar in mice and rats to that of CCNU, with the exception that, TCNU did not cause the chronic liver disturbances found for CCNU. In dogs treated for 6 weeks with TCNU leucopenia and thrombocytopenia were the major side effects. Parent TCNU was found in all dogs. The absorption was fast, the maximum level being reach after 25 mins and the mean absorption time was 22 mins. The mean half life was 16.1 mins after intravenous and 17.4 after oral administration. The combination of these factors make TCNU an interesting clinical candidate.

Modulation of 5-fluorouracil toxicity by uridine, deoxyuridine, orotate and dipyridamole in normal tissues of rats with liver adenocarcinoma.

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.

Incorporation of 5-fluorouracil into RNA of normal tissues and an adenocarcinoma in protein-deprived rats.

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.

Hepatic artery administration of degradable starch microspheres: II. Effects on incorporation of uridine and uracil into RNA of an adenocarcinoma transplanted to rat liver.

Effects of degradable starch microspheres administered via the hepatic artery were examined in rats in which an adenocarcinoma was transplanted into the liver. 3H-uridine or 3H-uracil with cold uridine and uracil, respectively, in amounts corresponding to therapeutic doses of these two pyrimidines as fluoro compounds, were administered with or without microspheres. Labeling of the acid-soluble fraction and RNA of tumor, liver, small intestine, spleen, kidney, and bone marrow was examined after 3 and 60 min after injection. When microspheres were added, the specific radioactivity of tumor RNA was significantly higher at both 3 min (P less than 0.05) and 60 min (P less than 0.01) in the rats given uridine, and in rats given uracil it was higher at 60 min after injection (P less than 0.05). There were no such differences in the labeling of the normal tissues. The results indicate that arterial administration of cytostatic drugs, such as 5-fluoropyrimidines, together with degradable starch microspheres might increase the cytotoxic effect on tumors nourished by the artery.

Effect of N-phosphonacetyl-L-aspartate and D-glucosamine on the incorporation of 5-fluorouridine into normal tissues and an adenocarcinoma in the rat.

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.

Isotachophoretic and HPLC determination of nucleotides in rat liver cell nuclei isolated by non-aqueous technique.

Rat liver whole cells and cell nuclei were prepared by a non-aqueous technique (glycerol). The nuclear preparations were of different purity as determined by RNA/DNA ratios (0.17-1.60) and accordingly were divided into 3 subgroups (mean values 0.29, 1.04 and 1.48). RNA nucleotides were separated by isotachophoresis and HPLC and calculated per mg DNA. Two of the nuclear subgroups (RNA/DNA = 1.04 and 1.48) had significantly elevated nucleotide values in relation to RNA/DNA. UDP-N-acetylhexosamine/DNA, on the contrary, was reduced in conformity with RNA in the preparations. Our findings may indicate different nucleotide concentrations in different parts of the cell.

Variation of incorporation of [3H]orotic acid into the nucleotide and RNA fractions of different parts of the same liver lobe in the rat.

1. Anaesthetized rats were given [3H]orotic acid either intraperitoneally or via a catheter into the hepatic artery with or without degradable starch microspheres. 2. The radioactivity in the acid soluble and RNA fractions of five pieces of the left lateral liver lobes was determined. 3. A variation of the distribution of the precursor into the different parts of the same liver lobe was shown. 4. This variation was most pronounced (3000-17,000 cpm/micrograms in the acid soluble fraction) when the precursor was administered via the artery and without microspheres. 5. The correlation between the radioactivity in the acid soluble and RNA fractions within each liver piece was 0.85, 0.90 and 0.75 in the three groups respectively. 6. It is suggested that the variation of the distribution depends on circulatory differences within the liver.

5-Fluorouracil incorporation into RNA of a rat liver adenocarcinoma after hepatic artery injection together with degradable starch microspheres.

The effect of degradable starch microspheres (DSM) on the cellular incorporation of 5-fluorouracil (FUra) was studied in rats with solitary liver tumours. 3H-labelled FUra [0.78 mg (6000 nmol)/kg b.wt.] was injected with saline or mixed with DSM, into the hepatic artery. Labelling of the acid soluble fraction (ASF), RNA and DNA of tumour, liver, bone marrow and small intestine was measured 60 minutes after injection. The DSM had no significant effect on the incorporation of FUra into the ASF or RNA, neither in tumour nor liver tissue. Regarding the tumour/normal tissue ratios of specific radioactivities, there was with DSM a higher tumour/liver and a higher tumour/bone marrow ratio in the ASF, indicating an increased tumour drug exposure with DSM. However, this was not accompanied by any significant increase in drug anabolism.

Mechanisms behind the inhibitory effect of ethanol on the conjugation of morphine in rat hepatocytes.

Liver microsomes were isolated by calcium aggregation, and isolated hepatocytes from male Wistar rats were prepared according to a two-step Ca++-free collagenase perfusion method. With the hepatocytes maximal inhibition of glucuronidation (about 40%) was reached at 10 mM ethanol after incubation at 37 degrees C for 60 min. UDP-glucuronic acid concentration and energy charge in the hepatocytes also did decrease maximally (about 90 and 50%, respectively) and the amount of UDP-glucose was tripled in the presence of 10 mM and higher concentrations of ethanol. The alcohol dehydrogenase inhibitor 4-methylpyrazole abolished ethanol-induced inhibition of morphine glucuronidation in the hepatocytes. Acetaldehyde (250-50 microM) and the pH decrease induced by ethanol did not reduce morphine-3-glucuronide formation by the cells. Cellular uptake of morphine and excretion of morphine metabolites were similar in the absence and presence of ethanol. Ethanol (60 mM) did not affect the glucuronidation of morphine (1.7 mM added) during a 30-min incubation at 37 degrees C with the microsomes (UDP-glucuronic acid, 5 mM). When the concentration of UDP-glucuronic acid in the microsomes was lowered from 1 to 0.1 mM, the decrease in morphine-3-glucuronide formation was similar to that observed in cells. The data indicate that the inhibition by ethanol of morphine glucuronidation was due to decreased levels of UDP-glucuronic acid. The mechanism is likely to be inhibition of UDP-glucose dehydrogenase activity by ethanol from increased intracellular NADH/NAD ratio accompanying ethanol oxidation.

Effect of hepatic artery ligation on the incorporation of 3H-orotic acid into an adenocarcinoma transplanted to rat liver.

In the model of secondary liver cancer in Wistar rats a study was made of the influence of hepatic artery ligation (HAL) on the amount of nucleotides and RNA in tumor and liver tissue and on the uptake of 3H-orotic acid into these compounds and DNA after labelling for 90 minutes. Ten days after inoculation with tumor cells into the central liver lobe, a catheter was placed into the portal vein in all rats and in half of them the hepatic artery was ligated. On days one, three, five or ten, rats were given 3H-orotic acid through the catheter. On day ten 3H-orotic acid was also infused via the femoral vein or intraperitoneally. After HAL there was a decrease in the nucleotide and RNA content of the tumor cells after one, three and five days. There was no such decrease in the liver cells. In all HAL rats there was an increase in the nucleotide and RNA content of the tumor cells at day ten compared to day five. The ratio of RNA to acid soluble fraction labelling in tumors was also increased on day ten in all groups compared to HAL rats at day five. The increased uptake of 3H-orotic acid into tumour RNA at day ten after HAL strongly suggests rearterialization. There was no support for an increased vascularization of the tumor from the portal vein on day three or five. In the liver tissue, HAL had no influence. This experimental study gives no support for the use of hepatic dearterialization followed by intraportal infusion av cytostatic agents in clinical settings.