Abnormalities in plasma and red blood cell fatty acid profiles of patients with colorectal cancer

Intravenous injection of stearoyl vanillylamide (C18-VA), a nonpungent capsaicin (CAP) analog, enhances adrenaline secretion significantly and as effectively as CAP in rats. Because swimming capacity was enhanced by CAP in mice due to CAP-induced adrenal catecholamine secretion, we investigated the effects of oral administration of C18-VA on swimming capacity using an adjustable-current water pool. Male Std ddY 6-wk-old mice were fed a commercial diet for this study and one group was orally administered C18-VA via a stomach tube. Treated mice were able to swim longer before exhaustion than the control mice (62.9 +/- 5.6 vs. 49.6 +/- 7. 0 min, P < 0.05). The swimming capacity of two groups administered C18-VA (0.02 and 0.033 mmol/kg) was significantly greater than that of those administered vehicle alone, (P < 0.05). Substance P concentration in cerebrospinal fluid, which is involved in pain transmission and is the first direct measure of pungency, was not affected by C18-VA administration. In an experiment examining the effects of C18-VA on serum adrenaline concentration, adrenaline was significantly greater in C18-VA treated mice than in controls at 2-h post-dose (C18-VA group, 26.09 +/- 2.82; control group 13.29 +/- 0. 96 microg/L, P < 0.01). In a separate study free fatty acids in serum were elevated in treated mice at 2-h post-dose (P < 0.01). While serum glucose concentration was not affected. These results suggest that C18-VA increased swimming capacity of mice via adrenaline release, independent of pungency. In addition, the present study suggests the usefulness of its application to humans.     

Comparison of 5-fluoro-2'-deoxyuridine with 5-fluorouracil and their role in the treatment of colorectal cancer

Despite more than 30 years of intensive studies on new drugs against advanced colorectal cancer, the fluoropyrimidines remain the drugs of choice for systemic treatment and for hepatic artery infusion (HAI). This overview describes new developments in advanced colorectal cancer chemotherapy, providing a rationale for more effective use of the fluoropyrimidines, with biochemical modulation, scheduling or by revealing biochemical mechanisms of action that correlate with antitumour activity. In human colorectal cancer cell lines and various animal tumour model systems 5-fluoro-2'-deoxyuridine (FdUrd) is more effective than 5-fluorouracil (5-FU). Comparably, FdUrd's modulation by leucovorin (LV) is more potent than 5-FU. In animal studies it is shown that intermittent high-bolus administration of FdUrd generates better antitumour activity, compared with equal toxic doses or any other schedule of 5-FU. These effects are related to prolonged-thymidylate synthase (TS) inhibition and the prevention of TS induction, rather than RNA incorporation. Preclinical studies with modulators such as N-phosphonacetyl-L-aspartate (PALA), WR-2721, mitomycin C and platinum derivatives provide a rationale for clinical use in the future. The first choice systemic chemotherapy of patients with advanced colorectal cancer remains 5-FU combined with LV. Some improvement in therapeutic efficacy has been achieved with locoregional HAI. In randomised studies HAI FdUrd improves the quality of life and survival as compared with optimal systemic therapy. Chronomodulation decreases toxicity, allowing dose intensification, while modulators such as LV or dexamethasone increase survival of patients treated with HAI FdUrd to 86% after 1 year. In conclusion, the clinical use of FdUrd has not been fully explored. Intermittent high-dose FdUrd, chronomodulation together with the use of modulators or drugs focused on prolonged TS inhibition, should be studied in large randomised studies.     

Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2''-tetrahydrofuryl)-5-fluorouracil

In order to examine the relationship between long-term potentiation (LTP) and phosphoinositide (PI) turnover, we evaluated these throughout anesthetized rat brain using carbon-11-labeled diacylglycerol (11C-DAG). High-frequency tetanic stimulation (400 pulses at 400 Hz) to the perforant pathway induced LTP in rat dentate gyrus. In autoradiograms of rat brains, LTP was associated with the occurrence of multiple highly radioactive spots in many regions distant from the stimulated site. Following i.v. administration of an NMDA receptor antagonist prior to stimulation, however, no high-density spots were found. These findings directly demonstrate that potentiation of phosphoinositide-derived signaling was induced during LTP, and the finding of multiple location suggests the occurrence of polysynaptic neurotransmission through neural networks pertaining to learning and memory.     

Treatment of advanced colorectal cancer with folinic acid and 5-fluorouracil in combination with cisplatinum

51 patients with metastatic colorectal cancer (stage Dukes D) were treated with intravenous (i.v.) infusion on days 1, 3, 5, 8 and 16 with folinic acid (200 mg/m2) and 5-fluorouracil (600 mg/m2), and on days 1, 8 and 16 with cisplatinum (25 mg/m2 i.v.); cycles were repeated every 4 weeks. All 51 patients were evaluable for toxicity and response criteria. 26 patients had objective responses (3 complete responses, 5.9%; 23 partial responses, 45.1%), relative risk 51% (95% confidence intervals 36.7-65.0%). Response duration ranged from 4 to 28.0 months (median 16.8). Overall median survival of all patients included was 14.7 months (range 3.0-33.0). Toxicity of WHO grade III, requiring dose reduction, occurred in 9 (18%) patients. The regimen described here appears to be active, safe and well tolerated for treatment of patients with advanced colorectal cancer.     

Continuous intra-hepatic-arterial infusion of low dose 5-fluorouracil for colorectal cancer patients with unresectable liver metastases

Five cases of colorectal cancer with unresectable liver metastases treated from April 1992 to April 1993 in Osaka National Hospital were summarized in this paper. A silicone catheter was placed in the hepatic artery through the gastroduodenal artery by operative procedure and connected to a subcutaneously implanted reservoir. 5-FU was administered ambulatorily using Baxter Infusor (multi day type) according to a regimen of 5-day continuous infusion and subsequent 2-day rest. The patients were 4 men and 1 woman, and from 51 to 65 years old (average: 62.4 y.o.). According to criteria for antitumor effectiveness by CT scan, one patient was judged CR, two were PR, and one was PD. One case could not be estimated because of catheter obstruction. The total efficacy rate was 75%. The serum CEA level was reduced in 3 patients. As for complication, obstruction of catheter, damage to reservoir and segmental necrosis of liver were observed in 3 patients. In conclusion, our ambulatory therapy for colorectal cancer patients with liver metastases was considered to have a high potential of not only effectiveness for cancer lesion but also the improvement of patients' quality of life.     

Combination hepatic intra-arterial 5-fluorouracil and CDDP administration with oral regimen in patients with colorectal cancer metastasis to the liver

We investigated therapeutic effectiveness and side effects of a combination weekly high-dose 5-FU plus one shot CDDP HAI (WHF + CDDP method) with oral regimen in patients with colorectal cancer metastasis to the liver. All 24 patients enrolled in this study showed 54% efficacy whereas patients combined HAI with oral regimen over one week obtained 83% efficacy for multiple liver metastasis. They showed good quality of the life during combination chemotherapy without any symptoms of metastatic lesions. The WHF + CDDP method combined with oral regimen is a promising treatment for colorectal cancer metastasis to the liver as well as extrahepatic distant organs, and this protocol may be satisfactorily accepted by most colorectal cancer laden patients because of negligible side effects.     

A phase II trial of weekly infusional 5-fluorouracil in combination with low-dose leucovorin in patients with advanced colorectal cancer

We examined 59 breast cancers for p53 and bcl-2 protein expression by immunohistochemistry. The results were correlated with Ki-67 immunostaining. p53-negativity was noted in 40 cases and the remaining 19 tumours were p53-positive. Thirty-six tumours showed strong expression of bcl-2 and in 23 no staining for this protein was observed. We found statistically significant reverse correlation between expression of p53 and bcl-2 in majority of carcinomas: 31 cases were bcl-2 positive and p53-negative, and 14 tumours were bcl-2-negative and p53-positive. Six carcinomas showed no nuclear staining for Ki-67 and in the remaining 53 the percent of cancer cells positive for Ki-67 ranged from 1 to 60 (mean: 14.6). In these 53 cases we found that bcl-2-positive tumours were characterized by lower proliferation than bcl-2-negative tumours, the mean value of Ki-67 immunostaining being 10.7% and 23.0%, respectively. p53-negative tumours showed lower proliferation than p53-positive tumours: mean Ki-67 index was 10.2% and 23.9%, respectively. We conclude that immunohistochemically detected p53 and bcl-2 proteins show a significant inverse relationship in majority of breast carcinomas and their expression correlates with tumour proliferation (Ki-67 immunostaining).     

Raltitrexed (Tomudex): an alternative drug for patients with colorectal cancer and 5-fluorouracil associated cardiotoxicity

Two patients with proven 5-fluorouracil (5-FU)-associated cardiotoxicity were treated with the specific thymidylate synthase inhibitor raltitrexed safely, without evidence of cardiotoxicity. Raltitrexed might be an alternative for patients with advanced colorectal cancer and 5-FU-associated cardiotoxicity. 5-FU cardiotoxicity is not due to the antineoplastic mechanisms via thymidilate synthase.     

Imipramine distribution among red blood cells, plasma and brain tissue

Hypertension complicates the treatment of anaemia of chronic renal failure with recombinant human erythropoietin (EPO) in some patients. We conducted a prospective study measuring changes in cardiac index (CI) and systemic vascular resistance index (SVRI) in 29 patients from before commencement of EPO to attainment of target haemoglobin concentration. We used the operator-independent technique of trans-thoracic bioimpedance. The group of patients who developed EPO-induced hypertension (EpHT) were separately analysed and compared with the group who had no change in blood pressure (NC). Our results showed there was a significant rise in SVRI after treatment in EpHT group patients but in the NC group there was a small fall. CI increased significantly in the NC group after treatment but no change was recorded in the EpHT group. These findings clearly demonstrate how the cardiovascular changes differ in patients who develop EPO-induced hypertension.     

Putative role of dihydropyrimidine dehydrogenase in the toxic side effect of 5-fluorouracil in colorectal cancer patients

Dihydropyrimidine dehydrogenase (DPD) is the first and rate limiting enzyme in the catabolism of 5-fluorouracil (5-FU). It has been reported from various laboratories that the plasma concentration of 5-FU was influenced by DPD activities in various normal human organs (e.g. liver or lymphocytes). Since the congenital deficiency in DPD caused severe, in some cases lethal, FU-related toxicity, it was decided to collect data about the DPD activity in colorectal cancer patients in order to investigate the possible correlation between the enzyme activity and appearance of the side effects of 5-FU. Assuming that DPD activity in lymphocytes represents the 5-FU catabolic capacity of the organism, DPD activity was determined in the lymphocytes of 48 patients with colorectal cancer after surgery during the therapeutic course with 5-FU and folinic acid. On the basis of the enzyme activity, patients were divided into three categories: low (DPD <5.03 pmol/min/10(6) lymphocytes); medium (DPD = 5.04-13.25 pmol/min/10(6) lymphocytes), and high (DPD > 13.26 pmol/min/10(6) lymphocytes) activity groups. By evaluating the toxic side effects during the 5-FU + folinic acid treatment, the following results were obtained. In the low DPD activity group, 9 of 11 patients had 5-FU-related side effects (mucositis, diarrhea, myelotoxicity, angina pectoris, hypertension). In 3 patients, no change of the therapy was needed, in 3 patients symptoms could be reversed by dose reduction of 5-FU while in 3 patients interruption of 5-FU therapy was needed. In the medium DPD activity group, mild toxicity (diarrhea, transitory hypertension) occurred in 5 of 29 and in the high activity group (diarrhea) in 1 of 8 patients, respectively. In these last two groups, no dose reduction of 5-FU was necessary. The present study furnished further evidence for the possible correlation between the 5-FU side effects and DPD function. Consequently, it is recommended to measure DPD activity prior to 5-FU based chemotherapy, which might be helpful in avoiding drug-related toxicity by adjusting the dose of 5-FU individually.     

Risk factors associated with mucositis in cancer patients receiving 5-fluorouracil

Oral mucositis is a dose-limiting toxicity of 5-fluorouracil (5-FU). This prospective cohort study investigated factors associated with mucositis in patients receiving 5-FU for cancer of the digestive tract. Sixty-three patients (mean age 65 years) completed self-administered questionnaires and had interviews, oral examinations and unstimulated whole salivary flow measurements at baseline and follow-up appointments. The duration of follow-up was 2 months. Predictor variables included sociodemographic data, body surface area, diabetes, smoking, alcohol consumption, salivary flow, oral hygiene, presence of prostheses, performance status, regimen of cytotoxic drugs, hematological data, and herpes simplex virus antibody titer. Forty-six per cent of patients developed at least one episode of oral mucositis during cytotoxic treatment. Pearson's chi-square analysis showed that mucositis was significantly associated with xerostomia at baseline, xerostomia during chemotherapy, and lower baseline neutrophil counts (P < or = 0.05). Multiple logistic regression analysis indicated that xerostomia at baseline (odds ratio, OR = 10.0), or baseline neutrophil level under 4000 cells/mm3 (OR = 3.9) were significant predictors of mucositis. Taking into account the effect of neutrophil level at baseline, xerostomia during chemotherapy (OR = 4.5) was also a significant predictor of mucositis. The results showed that xerostomia and lower baseline neutrophil levels are significantly associated with oral mucositis. These variables should be taken into consideration in the design of intervention studies to reduce the frequency and severity of mucositis. More research is required to investigate the role of saliva and neutrophils in the pathogenesis of chemotherapy-induced mucositis.     

Irinotecan and 5-fluorouracil in colorectal cancer: time for a pause?

OBJECTIVE: To evaluate the effects of administration of a sterically stabilized liposome-encapsulated cisplatin (SSL-CDDP) to cats. ANIMALS: 4 clinically normal cats. PROCEDURE: 2 of the cats were given multiple i.v. injections of SSL-CDDP at a dosage of 70 mg of free CDDP equivalent/m2 of body surface area at 3-week intervals. The other 2 cats received single i.v. injections of identical liposome preparations not containing CDDP. Vital signs; appetite; attitude; hematologic, serum biochemical, and urinalysis findings; and thoracic radiographic views were evaluated at predetermined intervals. RESULTS: Sterically stabilized liposome-encapsulated cisplatin was well tolerated by all cats. The only significant alterations in measured variables were an increase in serum cholesterol concentration 2 days after injection, and repeatable pyrexia in the cats receiving SSL-CDDP that began 10 to 12 hours after injection and continued for 18 hours, peaking at 40.5 to 41 C. Alterations in rectal temperature were not significant in cats receiving empty liposome vehicle. CONCLUSIONS: SSL-CDDP appears to be safe to administer to cats at a dosage of 70 mg of free CDDP equivalent/m2, a CDDP dose known to be therapeutic in dogs. Pyrexia, although marked, appears to be a short-term and well tolerated side effect. CLINICAL RELEVANCE: SSL-CDDP appears to abrogate the uniformly fatal side effects associated with administration of tumoricidal quantities of free CDDP to cats. This new formulation should allow investigation of the antitumor properties of CDDP against spontaneously arising neoplasms in cats.     

Cardiotoxicity of 5-fluorouracil in combination with folinic acid in patients with gastrointestinal cancer

BACKGROUND: Cardiotoxicity related to the widely used cytotoxic compound 5-fluorouracil (5-FU) is rare compared with the frequency observed with the use of anthracyclines. More effective protocols incorporating active biomodulatory compounds like folinic acid (FA) or combination chemotherapy change type and severity of toxicity as well. The objective of the current study was to assess cardiotoxicity of the combination 5-FU and folinic acid. METHODS: The authors' multicenter experience with 390 patients treated for advanced gastrointestinal cancer with intermediate-dose folinic acid and 5-FU was reviewed. RESULTS: The overall risk of cardiotoxicity was 3%, which is not significantly higher than that reported with 5-FU alone. Eight of 53 patients with a history of cardiac disease reported cardiac symptoms (15.1%), compared with 5 of 337 patients (1.5%) with a no history of cardiac disease. Median time to symptoms was 3 days (range, 2-6). Nine patients had symptoms resembling myocardial ischemia, one patient died due to assumed myocardial infarction related closely to fluorouracil treatment, four patients had supraventricular arrhythmia, and one patient had congestive heart failure. A history of cardiac disease was the only risk factor associated with cardiotoxicity. Relapses were frequent on reinstitution of therapy despite cardiac symptoms in the preceding cycle. Therapeutically or prophylactically administered nitrates had no significant effect. CONCLUSION: Physicians should be aware of the cardiotoxic properties of active fluorouracil treatment. The combination of 5-FU and leucovorin does not differ from single-agent therapy in frequency or type of cardiotoxicity. Close monitoring of patients is mandatory, especially for those patients at high risk for cardiac side effects. Treatment should be discontinued if coronary symptoms develop, because neither effective treatment nor prophylaxis exists for such symptoms.     

Red blood cell glutathione status in patients with gastrointestinal malignancies treated with 5-fluorouracil

As an alternative to surgical splenectomy, partial splenic embolization was performed in seven children for hypersplenism manifested by splenomegaly, thrombocytopenia, leukopenia, and erythrocyte hemolysis. Within a few days, platelet and leukocyte counts rose significantly in all patients and were maintained in six of seven patients during a follow-up period of 9 to 69 months. Spleen size and abdominal distention also decreased significantly in all children. There were no infectious complications.     

Effect of 5-fluorouracil and UFT on experimental liver metastasis model of colorectal cancer using mouse colon 26 cells

Effects of 5-fluorouracil (5-FU) and UFT on an experimental liver metastasis model were compared at equi-effective dosage levels against subcutaneous tumor of mouse colon 26. 5-FU at the dosage level of 40 mg/kg suppressed the subcutaneous tumor growth by 70.0% and 45.0% on day 13 and day 18, respectively, and UFT at 20 mg/kg provided almost equal suppression (63.0% and 48.0%). In the liver metastasis model, 5-FU at 40 mg/kg showed more potent prevention of the formation of metastatic foci (94.9%) than did UFT (60.4%) at 20 mg/kg. 5-FU at 40 mg/kg produced a much higher peak serum level of 5-FU than did UFT at 20 mg/kg and also showed a much higher AUC (area under the curve) level in the portal blood. These results suggest that oral administration of 5-FU might be useful in prevention of liver metastasis of colorectal cancer.