levoleucovorin and Body-Weight

Patients suffering from advanced colorectal cancer can experience unintended weight loss and/or treatment-induced gastrointestinal toxicity. Based on current evidence, the routine use of parenteral nutrition (PN) for patients with colorectal cancer is not recommended. This study evaluates the effect of PN supplementation on body composition, quality of life (QoL), chemotherapy-associated side effects and survival in patients with advanced colorectal cancer.. Eighty-two patients with advanced colorectal cancer receiving a palliative chemotherapy were prospectively randomized to either oral enteral nutrition supplement (PN-) or oral enteral nutrition supplement plus supplemental PN (PN+). Every 6 weeks body weight, body mass index (BMI), chemotherapy-associated side effects and caloric intake were assessed, haemoglobin and serum albumin were measured. Body composition was assessed by body impedance analysis, and QoL was evaluated by European Organization for Research and Treatment of Cancer (EORTC) QLQC30 questionnaire.. No differences were evident at baseline between the groups for age, sex, diagnosis, weight, BMI or QoL. A difference in BMI was observed by week 36, whereas differences of the mean body cell mass could be observed from week 6, albumin dropped significantly in the PN- group in week 36 and QoL showed significant differences from week 18. Chemotherapy-associated side effects were higher in PN-. The survival rate was significantly greater in the PN+ group.. A supplementation with PN slows weight loss, stabilizes body-composition and improves QoL in patients with advanced colorectal cancer. Furthermore, it can reduce chemotherapy-related side effects.

Topics: Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Body Composition; Body Weight; Carcinoma; Colorectal Neoplasms; Energy Intake; Energy Metabolism; Female; Fluorouracil; Hemoglobins; Humans; Kaplan-Meier Estimate; Leucovorin; Male; Malnutrition; Middle Aged; Palliative Care; Parenteral Nutrition; Prospective Studies; Quality of Life; Serum Albumin; Survival Analysis

The present study was conducted to evaluate activity and toxicity of the FLEC (folinic acid 100 mg/m2; 5-fluorouracil 1000 mg/m2; carboplatin 300 mg/m2; epirubicin 60 mg/m2) schedule as second-line treatment for progressive locally advanced or metastatic pancreatic cancer (LAMPC). FLEC was administered every 3 weeks with an angiographic catheter introduced into the tumor vascular bed. Thirty-two patients were enrolled. Twenty patients had a PS of 2. Twenty-five patients had metastatic disease to liver. Seven (21.9%) partial responses were observed (WHO criteria). Fifteen patients (46.9%) had stable disease and ten patients (31.2%) had progressive disease. The median OS from the diagnosis was 11.8 months. PS (p=0.0308) and pain (WHO scale, p=0.0222; analogic scale, p=0.0446) significantly improved after therapy. No patient discontinued treatment because of toxicity (NCI-CTC criteria). The current study shows that intraarterial chemotherapy is a good therapeutic option in second-line treatment of LAMPC.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carboplatin; Disease Progression; Epirubicin; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Leucovorin; Male; Middle Aged; Neoplasm Metastasis; Pancreatic Neoplasms; Retrospective Studies; Time Factors; Treatment Outcome

To develop and a priori validate a methotrexate population pharmacokinetic model in children with acute lymphoblastic leukaemia (ALL), receiving high-dose methotrexate followed by folinic acid rescue, identifying the covariates that could explain part of the pharmacokinetic variability of methotrexate.. The study was carried out in 49 children (aged 6 months to 17 years) who received high-dose methotrexate (3 g/m(2) per course) in long-term treatment. In an index group (37 individuals; 1236 methotrexate plasma concentrations), a population pharmacokinetic model was developed using a nonlinear mixed-effects model. The remaining patients' data (12 individuals; 278 methotrexate plasma concentrations) were used for model validation. Age, sex, total bodyweight (TBW), height, body surface area, lowest urine pH during infusion, serum creatinine, ALT, AST, folinic acid dose and length of rescue were analysed as possible covariates. The final predictive performance of the pharmacokinetic model was tested using standardised mean prediction errors.. The final population pharmacokinetic model (two-compartmental) included only age and total bodyweight as influencing clearance (CL) and volume of distribution of central compartment (V(1)). For children aged < or =10 years: CL (L/h) = 0.287 . TBW(0.876); V(1) (L) = 0.465 . TBW, and for children aged >10 years: CL (L/h) = 0.149 . TBW; V(1) (L) = 0.437 . TBW. From the base to the final model, the inter-individual variabilities for CL and V(1) were significantly reduced in both age groups (30-50%). The coefficients of variation of the pharmacokinetic parameters were <30%, while residual and inter-occasional coefficients maintained values close to 40%. Validation of the proposed model revealed the suitability of the model.. A methotrexate population pharmacokinetic model has been developed for ALL children. The proposed model could be used in Bayesian algorithms with a limited sampling strategy to estimate the systemic exposure of individual patients to methotrexate and adapt both folinic acid rescue and methotrexate dosing accordingly.

Topics: Adolescent; Age Factors; Alanine Transaminase; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Aspartate Aminotransferases; Bayes Theorem; Body Weight; Child; Child, Preschool; Creatinine; Dose-Response Relationship, Drug; Female; Humans; Infant; Infusions, Intravenous; Leucovorin; Male; Metabolic Clearance Rate; Methotrexate; Models, Biological; Monte Carlo Method; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Treatment Outcome; Vitamin B Complex

Obesity is a risk factor for the development of colon carcinoma. The influence of body mass index (BMI) on long-term outcomes and treatment-related toxicity in patients with colon carcinoma has not been well characterized.. This cohort study was conducted within a large, randomized adjuvant chemotherapy trial of 3759 men and women with high-risk, Stage II and Stage III colon carcinoma who were treated between 1988 and 1992 throughout the United States. With a median follow-up of 9.4 years, the authors examined the influence of BMI on disease recurrence, overall survival, and treatment-related toxicity.. Compared with women of normal weight (BMI, 21.0-24.9 kg/m(2)), obese women with colon carcinoma (BMI > or = 30.0 kg/m(2)) experienced significantly worse overall mortality (hazard ratio [HR], 1.34; 95% confidence interval [95% CI], 1.07-1.67) and a nonsignificant increase in the risk of disease recurrence (HR, 1.24; 95% CI, 0.98-1.59). The influence of BMI among women was not related to any differences in chemotherapy dose-intensity across categories of BMI. In contrast, BMI was not related significantly to long-term outcomes among male patients in this cohort. Among all study participants, obese patients had significantly lower rates of Grade 3-4 leukopenia and lower rates of any Grade > or = 3 toxicity compared with patients of normal weight.. Among women with Stage II-III colon carcinoma, obesity was associated with a significant increase in overall mortality as well as a borderline significant increase in disease recurrence. Nonetheless, obesity was not associated with any increase in chemotherapy-related toxicity.

Topics: Antineoplastic Combined Chemotherapy Protocols; Body Mass Index; Body Weight; Chemotherapy, Adjuvant; Cohort Studies; Colonic Neoplasms; Female; Fluorouracil; Follow-Up Studies; Humans; Leucovorin; Levamisole; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Obesity; Risk Factors; Survival Rate; Treatment Outcome; United States

Twenty-two patients, with locally advanced unresectable and/or metastatic pancreatic carcinoma, received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 mg m(-2), supported by a daily administration of lenograstim at a dose of 5 microg kg(-1). Nineteen patients were men and three were women. Median age was 63 years (range 47-70). At study entry, pain was present in 15 out of 22 patients (68%) with a mean value of Scott-Huskisson scale of 27.6+/-23.8, whereas a weight loss >10% was present in 15 patients. After eight weekly treatments, three partial responses were achieved for a response rate of 13% (95% CI 0-26%), five patients had stable disease and 14 progressed on therapy. Pain was present in 9 out of 22 patients (40%) with a mean value of Scott-Huskisson scale of 12.3+/-18.4. Eight patients (36%) (three partial response and five stable disease) had a positive weight change. Toxicity was mild: WHO grade III or IV toxicity was recorded in terms of anaemia in 7 out of 188 cycles (3.7%), of neutropenia in 9 out of 188 cycles (4.7%) and of thrombocytopenia in 3 out of 188 cycles (1.5%). Median survival of all patients was 6 months. The outcome of this intensive chemotherapy regimen does not support its use in pancreatic cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Carcinoma; Cisplatin; Drug Administration Schedule; Epirubicin; Female; Fluorouracil; Granulocyte Colony-Stimulating Factor; Humans; Lenograstim; Leucovorin; Male; Middle Aged; Pain; Palliative Care; Pancreatic Neoplasms; Recombinant Proteins; Survival Analysis; Treatment Outcome

The treatment-associated toxicity in 189 patients entered in the COSS-80 Study was analyzed. The sequential use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and cis-platinum may be additive or synergistic in causing renal toxicity. However, evaluation of the 48-h serum methotrexate level and the incidence of elevated serum creatinine levels throughout treatment failed to indicate prolonged methotrexate elimination or severe kidney damage from this regimen where an interval of 3 weeks between cis-platinum administration and the next course of HDMTX was mandatory. The treatment-related mortality was 3.2% (6 out of 189 patients). Three patients died of septicemia during chemotherapy-induced bone-marrow depression following treatment with adriamycin or the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). Three deaths occurred following the use of high-dose methotrexate with citrovorum factor rescue. Two of these deaths were associated with delayed excretion of methotrexate. The toxicity is within the range reported in the literature.

Topics: Acute Kidney Injury; Adolescent; Adult; Antineoplastic Agents; Body Weight; Bone Neoplasms; Child; Child, Preschool; Cisplatin; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Leucovorin; Leukopenia; Male; Methotrexate; Osteosarcoma

The aim of the present study was to determine the efficacy of trabectedin combined with FOLFIRI (irinotecan, leucovorin and 5-fluorouracil) on a colorectal cancer (CRC) patient-derived orthotopic xenograft (iPDOX) mouse model.. A CRC tumor from a patient previously established in nude mice was implanted subcutaneously in transgenic green fluorescence protein (GFP)-expressing nude mice in order to label the tumor stromal cells with GFP. Mice were randomized into four groups: Group 1, untreated control; group 2, FOLFIRI; group 3, trabectedin alone; group 4, trabectedin plus FOLFIRI. Tumor width, length, and mouse body weight was measured twice every week.. All three treatment groups showed inhibited tumor growth compared to the untreated control group. Only the combination of FOLFIRI and trabectedin arrested tumor growth. No significant changes was observed in body weight in any group.. These findings suggest that the combination of trabectedin plus FOLFIRI has clinical potential for patients with CRC.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Camptothecin; Colorectal Neoplasms; Fluorouracil; Green Fluorescent Proteins; Humans; Leucovorin; Mice; Mice, Nude; Mice, Transgenic; Random Allocation; Trabectedin; Tumor Burden; Xenograft Model Antitumor Assays

To assess the impact of chronomodulated irinotecan fluorouracil-leucovorin and oxaliplatin (chronoIFLO4) delivered at home on the daily life of patients with cancer in real time using a home-based e-Health multifunction and multiuser platform. This involved multidimensional telemonitoring of circadian rest-activity rhythm (CircAct), sleep, patient-reported outcome measures, and body weight changes (BWCs).. Patients received chronoIFLO4 fortnightly at home. Patients completed the 19-item MD Anderson Symptom Inventory on an interactive electronic screen, weighed themselves on a dedicated scale, and continuously wore a wrist accelerometer for CircAct and sleep monitoring. Daily data were securely teletransmitted to a specific server accessible by the hospital team. The clinically relevant CircAct parameter dichotomy index I < O and sleep efficiency (SE) were calculated. The dynamic patterns over time of patient-reported outcome measures, BWC, I < O, and SE informed the oncology team on tolerance in real time.. The platform was installed in the home of 11 patients (48 to 72 years of age; 45% men; 27% with performance status = 0), who were instructed on its use on site. They received 26 cycles and provided 5,891 data points of 8,736 expected (67.4%). The most severe MD Anderson Symptom Inventory scores were: interference with work (mean: 5.1 of 10) or general activity (4.9), fatigue (4.9), distress (4.2), and appetite loss (3.6). Mean BWC was -0.9%, and mean SE remained > 82%. CircAct disruption (I < O ≤ 97.5%) was observed in four (15%) cycles before chronoIFLO4 start and in five (19%) cycles at day 14.. The patient-centered multidimensional telemonitoring solution implemented here was well accepted by patients receiving multidrug chemotherapy at home. Moreover, it demonstrated that chronoIFLO4 was a safe therapeutic option. Such integrated technology allows the design of innovative management approaches, ultimately improving patients' experience with chemotherapy, wellbeing, and outcomes.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Circadian Rhythm; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Irinotecan; Leucovorin; Male; Middle Aged; Oxaliplatin; Pancreatic Neoplasms; Patient Reported Outcome Measures; Patient-Centered Care; Pilot Projects; Sleep; Survival Analysis; Telemedicine; User-Computer Interface

To investigate the ability of leucovorin (LV) to abrogate dose-limiting toxicities of pralatrexate (PDX) while maintaining efficacy, in vivo.. H2052 mesothelioma cells were treated with the antifolates methotrexate (MTX), PDX and pemetrexed, with and without LV rescue 24 h later. Cell killing was evaluated 48 h later. Female nude mice bearing H2052 xenografts were treated with varying doses and schedules of the antifolate PDX and LV.. In vitro, H2052 cells were more sensitive to PDX as compared to MTX and pemetrexed. Administration of LV 24 h after antifolate treatment reduced efficacy of antifolates MTX and pemetrexed, but not PDX. In vivo, LV was found to reduce toxicity of PDX at the maximum tolerated dose without sacrificing efficacy. Lethal doses of PDX were rescued by LV, and mice bearing the H2052 tumor demonstrated prolonged and enhanced tumor regression.. High-dose PDX with subsequent LV rescue may be a viable treatment strategy in mesothelioma and other cancers. The inclusion of LV rescue into new and existing PDX treatment protocols should be explored as a way to expand the tolerability and effectiveness of PDX in the clinic.

Topics: Aminopterin; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Drug Synergism; Female; Folic Acid Antagonists; Glutamates; Guanine; Humans; Leucovorin; Mesothelioma; Methotrexate; Mice, Nude; Pemetrexed; Time Factors; Tumor Burden; Vitamin B Complex; Xenograft Model Antitumor Assays

Amifostine has been shown to be capable of minimizing radiotherapy-induced oral mucositis, but whether it protects small intestinal mucosae from high-dose methotrexate-induced damage is presently unknown.. We aimed to evaluate the protective effect of amifostine against high-dose methotrexate-induced small intestinal mucositis and its mechanism.. Ninety Kunming mice were randomly divided into five experimental groups: saline control; high-dose methotrexate (HDMTX) group: treated with a single high dose of methotrexate; calcium folinate (CF) group: treated with high-dose methotrexate followed with CF; Amifostine group: treated with amifostine, followed with high-dose methotrexate; and amifostine-CF group: treated with amifostine pre-high-dose methotrexate and followed by CF post-high-dose methotrexate. Mouse weight, villus height and crypt depth, stool consistency, white blood cell count, death and survival were recorded. Bax and Bcl-2 mRNA expression were quantified by semi-quantitative PCR.. Compared to the mice treated with HDMTX, CF, and amifostine, mice treated with Amifostine-CF group were heavier and had greater villus height, crypt depth, and normal white blood cell count and lower diarrhea rate and mortality than the HDMTX, CF and amifostine groups. There was a significant decrease in enterocyte apoptosis in amifostine-CF mice compared with the HDMTX and CF groups.. The effect of amifostine plus CF was greater than amifostine or CF alone in preventing high-dose methotrexate-induced intestinal mucositis and improving intestinal recovery in mice.

Topics: Amifostine; Animals; Body Weight; Female; Immunosuppressive Agents; Intestine, Small; Leucovorin; Male; Methotrexate; Mice; Mucositis; Radiation-Protective Agents; Random Allocation; Specific Pathogen-Free Organisms

Human colon cancer cells were injected subcutaneous in nude mice. After 8 days the animals were divided in two groups, the first group received triple therapy with octreotide, galanin and serotonin (40 microg/kg body weight/day) through an ALZET osmotic pump implanted intraperitoneally (i.p.) for 14 days, followed by 5 days of subcutaneous injections (200 microg/kg body weight/ day). The second group was injected i.p. for 5 days with 5-fluorouracil/leukovorin (5-FU/LV) at concentrations of 4 mg and 2 mg/kg body weight, respectively. After 9 days without any treatment, the mice received i.p. injection with 5-FU/LV (20 mg and 10 mg/kg body weight/day, respectively) for another 5 days. The volume and weight of the tumours were measured at the end of the experiment. Apoptosis, proliferation, blood vessels, epidermal growth factor (EGF) and vascular endothelial cell growth factor (VEGF) were detected with immunocytochemistry. Apoptosis was also detected using the TUNEL-method. Quantification was performed using computed image analysis. There was no statistical significance between tumours treated with 5-FU/LV or triple therapy regarding the volume and weights of the tumours, apoptotic, proliferation, VEGF indces and the density of tumour blood vessels. The EGF labelling index was, however significantly lower in the tumours treated with triple therapy than those treated with 5-FU/LV. In conclusion, treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable with 5-FU/LV that is the standard chemotherapeutic agent for colorectal cancer.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Body Weight; Cell Line, Tumor; Cell Proliferation; Colonic Neoplasms; Epidermal Growth Factor; Fluorouracil; Galanin; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Leucovorin; Mice; Mice, Nude; Neovascularization, Pathologic; Octreotide; Platelet Endothelial Cell Adhesion Molecule-1; Poly(ADP-ribose) Polymerases; Serotonin; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

The administration of 5-fluorouracil (FU) and leucovorin (LV) to rats induced a previously unreported sialoadenitis-like toxicity. Four different treatment regimens were used: daily-times-5 iv or ip injections of LV (200 mg/kg) followed 30 minutes later by FU (27.5 mg/kg or 35 mg/kg). These treatments resulted in 3 severity levels of systemic toxicity indicated by changes in body weight. In addition to the well known FU+LV-induced diarrhea, myelosuppression, and stomatitis, facial edema, and enlargement of the submandibular salivary gland were consistently seen. Facial edema occurred almost exclusively in rats that subsequently underwent excessive weight loss and were euthanized. The submandibular, but not parotid or sublingual, salivary gland was enlarged and the severity of this effect changed in a bell-shaped relationship with respect to increasing FU+LV induced loss of body weight. Histologic examination of affected glands established the occurrence of bacterial infection, sialoadenitis and destruction of gland tissue. This paper provides the first known documentation of FU+LV treatment-induced selective pathology of the submandibular salivary gland. The selectivity of this toxicity, apparently not normally seen in humans, to the submandibular salivary gland of the rat is of interest and its mechanism warrants further investigation.

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Bone Marrow Cells; Dose-Response Relationship, Drug; Drug Therapy, Combination; Edema; Erythroid Cells; Female; Fluorouracil; Hematocrit; Hemoglobins; Injections, Intraperitoneal; Injections, Intravenous; Leucovorin; Leukocytes; Rats; Rats, Inbred F344; Submandibular Gland

Human colon cancer cells were injected sub-cutaneously into 30 nude mice. After 8 days, the animals were divided into 3 equal groups. The first and second groups received an i.p. injection with 5-fluorouracil/leukovorin (5-FU/LV) for 5 days (20 mg and 10 mg/kg body weight respectively). On the first day of 5-FU/LV treatment, the first group received an i.p. injection of irinotecan (2.5 mg/kg body weight), and the second group received an i.p. injection with oxaliplatin (1 mg/kg body weight). The third group were injected i.p. with 100 microl saline solution containing octreotide, galanin and serotonin. Injections were given 3 times daily for 5 days with a total dose of 150 microg/kg body weight/day. Three days after the treatment, the animals were sacrificed. Whereas the animals treated with triple therapy held a stable body weight, animals treated with 5-FU/LV-irinotecan and 5-FU/LV-oxaliplatin had gradual weight loss, which amounted to approximately 25% of their body weight at the end of the experiment. Moreover, 2 mice in the group treated with 5-FU/LV-irinotecan died, most probably due to side effects. There was no statistically significant difference between the 3 groups regarding tumour proliferation, apoptosis, blood vessel density, EGF- and VEGF-expression. Treatment with triple therapy using octreotide, galanin and serotonin appear to be comparable to 5-FU/LV in combination with irinotecan and oxaliplatin. However, triple therapy seems to have a better safety profile.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Body Weight; Camptothecin; Cell Proliferation; Colonic Neoplasms; Epidermal Growth Factor; Female; Fluorouracil; Galanin; Immunohistochemistry; In Situ Nick-End Labeling; Irinotecan; Leucovorin; Mice; Mice, Inbred BALB C; Mice, Nude; Neovascularization, Pathologic; Octreotide; Organoplatinum Compounds; Oxaliplatin; Platelet Endothelial Cell Adhesion Molecule-1; Poly(ADP-ribose) Polymerases; Serotonin; Time Factors; Treatment Outcome; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

Leucovorin (LV)/5-fluorouracil combination is one of the first-line forms of chemotherapy for colorectal cancer, and in this regimen it was recommended that 5-FU be infused continuously from the venous route. However, since this regimen limits the patients' ADL, oral administration is preferable. The purpose of this study is to elucidate the mechanisms of orally-administered LV/5-FU.. The Gastrostomy was performed, and 1 x 10(6) of colon 26 was transplanted subcutaneously in CDF1 mice. In the continuous administration group, either 10, 20, 40 mg/kg of 5-FU and 100 mg/kg of LV were continuously infused for 7 days following gastrostomy using a microinfusion pump (n = 6). In the single infusion group, either 10, 20, 40 mg/kg of 5-FU was infused once a day for 7 days after gastrostomy concomitant with LV (n = 6). The other 6 animals served as the control, and LV alone was infused in this group. Tumor volume, thymidylate synthase inhibition rate (TSIR), incorporation of 5-FU into RNA (F-RNA) and body weight were measured at the end of the treatment. During the experimental period, mice were given free access to chow and water.. The tumor volume suppression rate was significantly higher along with the amount of 5-FU. However, there was no significant difference between continuous and single infusion groups. TSIR was higher in the continuous group at the dose of 20 and 40 mg/kg. In contrast, F-RNA was higher in the single group at the dose of 20 and 40 mg/kg. Significant body weight loss was not recognized in any group.. From these data, single administration of 5-FU is more effective for RNA dysfunction. On the other hand, continuous infusion is more damaging to DNA duplication. In summary, since the mechanism of the antitumor effect differs with the administration method, it is important to understand this mechanism.

Topics: Administration, Oral; Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Colonic Neoplasms; Drug Administration Schedule; Fluorouracil; Leucovorin; Mice; Thymidylate Synthase

To verify whether fluorouracil (FU) clearance (CL) and volume of distribution (V(ss)) are better correlated with specific body compartments, such as body cell mass (BCM), total body water (TBW) or fat free mass (FFM), rather than with body surface area (BSA) or total body weight (BW).. Thirty-four patients (13 females and 21 males) affected by colorectal cancer and receiving FU as adjuvant therapy entered the study. CL and Vss were determined after a 2 min i.v. injection of FU (425 mg m(-2)) and leucovorin (20 mg m(-2)). Body composition, in terms of BCM, TBW and FFM, was evaluated non-invasively by bioelectrical impedance analysis (BIA).. Significant but poor correlations were found between CL or V(ss) and most anthropometric parameters, including BIA-derived measures (r2 range=0.10-0.21). However, when multiple regression analysis was performed with sex, TBW and FFM as independent variables, the correlations improved greatly. The best correlation was obtained between CL and sex (r2=0.44) and between V(ss) and sex (r2=0.36). FFM-normalized CL was significantly higher in women than in men (0.030+/-0.008 vs 0.022+/-0.005 l min(-1) kg)(-1); 95% CI of difference 0.012, 0.003; P=0.003), suggesting that FU metabolism is more rapid in females. Surprisingly, V(ss) was highly correlated with CL (r2=0.67; CL=0.52+V(ss) x 0.040). This finding may either be explained by extensive drug metabolism in extra-hepatic organs or by variable inactivation on first-pass through the lung. Both these hypotheses need experimental validation.. The pharmacokinetics of FU are better predicted by FFM and TBW than by standard anthropometric parameters and predictions are sex-dependent. The use of BIA may lead to improved dosing with FU.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Body Composition; Body Surface Area; Body Water; Body Weight; Colorectal Neoplasms; Electric Impedance; Female; Fluorouracil; Humans; Leucovorin; Male; Middle Aged; Predictive Value of Tests; Sex Factors

Intraperitoneal chemotherapy with 5-fluorouracil (5-FU) is a new, promising alternative in adjuvant treatment of advanced colorectal cancer. Leucovorin (LV), a biomodulator of 5-FU, potentiates the antineoplastic effect of 5-FU. The aim of this study was to determine whether the administration routes of LV had any influence on the impairment of colonic healing caused by intraperitoneal 5-FU treatment. 48 male Wistar rats were subjected to left colonic resection and anastomosis, and randomized to 1 of 4 groups: control group (receiving intraperitoneal NaCl, intravenous NaCl); ipFU group (receiving intraperitoneal 5-FU, intravenous NaCl); ipFU+ivLV group (receiving intraperitoneal 5-FU, intravenous LV), and ipFU+LV group (receiving intraperitoneal 5-FU+LV, intravenous NaCl). Treatment was started after surgery and continued for 5 days with daily injections. The animals were sacrificed on the 7th day postoperatively. Anastomotic complications were more common in the ipFU, ipFU+ivLV, and ipFU+LV groups (p < 0.05) compared to the control group. The anastomotic breaking strength was significantly reduced in the ipFU, ipFU+ivLV, ipFU+LV groups (p < 0.05) than in the control group, but it did not differ between the ipFU, ipFU+ivLV, and ipFU+LV groups. The hydroxyproline content of the anastomotic segment was also significantly reduced in the ipFU, ipFU+ivLV and ipFU+LV groups (p < 0.05) compared to the control group. However, there was no difference between the anastomotic hydroxyproline content of the ipFU, ipFU+ivLV, and ipFU+LV groups. In this experiment, colonic healing was impaired after intraperitoneal 5-FU administration as judged by the higher rates of anastomotic complications, reductions in anastomotic breaking strength and hydroxyproline content; but LV administration either intravenously or intraperitoneally did not cause further deterioration in colonic healing.

Topics: Anastomosis, Surgical; Animals; Antimetabolites, Antineoplastic; Blood; Body Weight; Colon; Fluorouracil; Hydroxyproline; Injections, Intraperitoneal; Leucovorin; Male; Rats; Rats, Wistar; Tensile Strength; Wound Healing

The objective of this study was to investigate whether folinic acid supplementation would protect young mice against suppression of growth by methotrexate (MTX). Four equal groups of Balb/c young male mice (5 animals in each group; mean+/-SD body weight 9.64+/-0.85 g, in their rapid growth phase) were subjected to the following drug treatment: One group was given MTX (3.5 mg/kg body weight) intraperitoneally on every 2nd day, another received folinic acid (7.0 mg/kg body weight) intraperitoneally every 2nd day. The third group was given both of these drugs (MTX on every 2nd day and folinic acid 8 h post-MTX injection). The fourth group was injected with physiological saline every other day to serve as a control group. Total body weight, food and water consumption by animals in each group were monitored every second day for a period of 3 weeks. After this period mice were sacrificed and liver, spleen and kidneys were excised, weighed and analyzed for MTX and dihydrofolate reductase activity. A small segment of the proximal part of small intestine and small pieces of liver and kidney were also removed to study morphological changes. Compared to the groups, which received folinic acid alone, folinic acid plus MTX or physiological saline, mean increase in body weight (6.8+/-0.8 g) of mice over a period of 3 weeks was minimal in the group receiving MTX alone (one-way ANOVA p=0.0001). The mean weights of liver and kidney in this group receiving MTX alone were also found to be significantly less than the mean weights of these organs in the 3 groups (p<0.001). The negative effect on growth of animals appears not only due to malabsorption but inhibition of pathway of de novo DNA synthesis may also be involved. This is supported by loss of villous pattern in small intestine of mice treated with MTX alone and increased accumulation of free MTX and decreased dihydrofolate reductase in the liver of the group receiving MTX alone as compared with the group receiving MTX plus folinic acid. The data indicate that the administration of folinic acid protects mice against suppression of growth by MTX. On the basis of these observations it can be deduced that patients suffering from juvenile rheumatoid arthritis or acute lymphoblastic leukaemia receiving MTX over a long period of time might be at a risk of experiencing short-term suppression of growth, however they could benefit from supplementation with folinic acid.

Topics: Animals; Antidotes; Body Weight; Eating; Folic Acid Antagonists; Growth Disorders; Intestine, Small; Kidney; Leucovorin; Liver; Male; Methotrexate; Mice; Mice, Inbred BALB C; Tetrahydrofolate Dehydrogenase

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor that is effective for the treatment of advanced colorectal cancer and other solid tumors. However, a small minority of patients receiving RTX monotherapy will experience grade III/IV gastrointestinal toxicity that can be life-threatening, particularly if copresenting with neutropenia. Lack of vigilance in recognition and treatment of symptoms of toxicity or violations of protocol have led to treatment-related deaths in some hospitals. The safety of RTX could be improved if an effective rescue agent was available. Leucovorin (LV) is a reduced folate cofactor that competes with RTX for transport and polyglutamation in both tumor and normal tissues and thus has potential as a rescue agent. In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV. The mechanisms involved are inhibition of further drug uptake and polyglutamation and a redistribution and/or reduction in the concentration of preformed raltitrexed polyglutamates. A more clinically relevant in vivo mouse model was used to test the hypothesis further. BALB/c mice treated with 100 mg/kg/day x 4 days of RTX were used as a model for gastrointestinal and bone marrow toxicity. LV (200 mg/kg), which was given after the onset of severe weight loss and diarrhea (twice daily, days 5-7), prevented further weight loss and induced earlier recovery. This was accompanied by improvement in the histological appearance of the intestine (day 7) and the concentration of neutrophils and platelets in the blood (day 9). BALB/c mice could not tolerate 100 mg/kg daily x 5 days unless LV (200 mg/kg twice daily) was given on days 6-8. Measurement of RTX (polyglutamates) by RIA after 100 mg/kg RTX daily (days 1-4) showed less drug in plasma (3-4-fold), liver (8-11-fold), kidney (3-4-fold), and small intestinal epithelium (3-4-fold) on day 7 in LV-treated mice (100 or 200 mg/kg twice daily) compared with controls. A single injection of 100 mg/kg RTX (day 1) gave plasma levels of 3-4 pmol/ml on day 4 that are more clinically relevant. Administration of LV (100 or 200 mg/kg; twice daily on days 4-6) reduced the RTX concentration in the liver 2-4-fold on days 7, 9, and 11 compared with controls. A model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the hom

Topics: Animals; Antimetabolites, Antineoplastic; Body Weight; Cell Division; Cell Line; Drug Interactions; Humans; Intestinal Mucosa; Intestine, Small; Leucovorin; Leukemia L1210; Lymphocytes; Male; Mice; Mice, Inbred BALB C; Neutropenia; Polyglutamic Acid; Quinazolines; Thiophenes; Thrombocytopenia

To clarify whether levofolinate calcium (1-LV) enhances 5-fluorouracil (5-FU) toxicity, a 4-week toxicity study of 5-FU (10 mg/kg/day) in combination with 1-LV (6, 20 or 60 mg/kg/day) was conducted in rats. In the 5-FU alone group, a decrease in body weight gain, food consumption, RBC parameter and WBC counts were detected. Histopathologically, lymphoid depletion of lymphatic organs, hematopoiesis enhancement of the spleen and myelosuppression were observed. In the group for which 5-FU was combined with 1-LV, the RBC counts decreased, extramedullary hematopoiesis increased and the suppression of lymphatic organs was enhanced. Changes in the lymphatic organs were observed at 20 mg/kg/day of 1-LV and above. In monitoring of blood drug concentrations of 1-LV, 5-methyl tetrahydrofolic acid, a metabolite of 1-LV, and 5-FU after the 1st and 14th dosings, there was no apparent difference between 5-FU alone and 5-FU combined with 1-LV in Cmax and AUC0-infinity. The potentiation induced by 1-LV in the toxicity of 5-FU appeared to be mainly immuno-suppression and myelosuppression, which were related to the anti-tumor activity of 5-FU. Plasma concentrations of 5-FU and 1-LV in this study overwhelmed the concentrations that enhancement of thymidylate synthetase (TS) inhibition due to 5-FU was observed by addition of 1-LV in vitro. Therefore toxic potentiation of 5-FU due to simultaneous 1-LV dosing is presumed to be concerned with an increased ternary complex (FdUMP-TS-5,10-methylenetetrahydrofolate) formation and a greater extent of TS inhibition.

Topics: Animals; Antidotes; Antimetabolites, Antineoplastic; Body Weight; Bone Marrow; Drug Synergism; Eating; Erythrocyte Count; Female; Fluorouracil; Injections, Intravenous; Isomerism; Kidney; Leucovorin; Leukocyte Count; Lymph Nodes; Male; Rats; Spleen

Potentiation of the anti-tumor activity of 5-fluorouracil (5FU) by methotrexate (MTX) and leucovorin (LV) requires careful scheduling to achieve the most favorable interactions between these 3 drugs. In vitro the triple combination of MTX/5FU/LV was tested at 4 time intervals and with 3 MTX concentrations in 3 cell lines. MTX/5FU/LV was never superior to both 5FU/LV and MTX/5FU, moreover LV reduced growth inhibition by MTX/5FU in 2 cell lines. MTX/5FU was associated with only moderately increased levels of the 5FU metabolite FdUMP, while LV/5FU reduced the free FdUMP levels. MTX/LV/5FU had a dual effect and FdUMP levels gave no clear indication regarding the anti-proliferative effect that could be expected. In vivo the time-dependent potentiation of MTX on the 5FU anti-tumor activity was confirmed for the treatment of HNX-14C-bearing mice. Addition of LV to the MTX/5FU combination failed to cause a gain in anti-tumor efficacy. For the treatment of Colon-26-bearing mice, MTX/5FU was comparable to LV/5FU, but the triple combination of MTX/LV/5FU seemed to have a better anti-tumor effect. However, the toxicity of the latter treatment was greater than that of LV/5FU. The data from both in vitro and in vivo experiments failed to support the addition of LV to MTX/5FU therapy, possibly due to a reversing effect of LV.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Cell Division; Female; Fluorodeoxyuridylate; Fluorouracil; Humans; Leucovorin; Methotrexate; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Transplantation; Neoplasms, Experimental; Tumor Cells, Cultured

The purpose of this investigation was to determine whether antitumor selectivity of the third generation thymidylate synthase inhibitor 1843U89 could be enhanced by a combination of the drug with folic acid. The effects of folic acid on toxicity of 1843U89 to the dog and mouse and on antitumor efficacy of 1843U89 in the mouse were studied. These data were compared to the effect of folic acid on the in vitro cell culture antitumor activity of 1843U89. The sensitivity of eight cancer cell lines (three ovarian, one colon, one ileocecal, one epidermoid, one osteosarcoma, and one breast line) to 1843U89 was tested in vitro in the presence and absence of folic acid. Folic acid concentrations greater than 100 microM were required to decrease 1843U89 activity in seven of the cell lines. Only the activity in HCT-8, the ileocecal line, was reserved at folic acid concentrations below 100 microM. Oral folic acid given 30 min prior to an i.v. dose of 1843U89 increased the maximally tolerated dose and the lethal dose of 1843U89, both in dogs and in thymidine-depleted mice. In mice, oral folic acid produced little or no effect upon the antitumor efficacy of 1843U89 in two of three tumor cell lines in vivo. HCT-8, the line that was sensitive to folate reversal in vitro, was also sensitive in vivo. The results show that an oral dose of folic acid 30 min prior to i.v. 1843U89 can block mouse and dog intestinal toxicity without decreasing efficacy of 1843U89 in two of three human tumor lines in the nude mouse. Thus, the data reported here indicate that the antitumor selectivity of 1843U89 may be enhanced through a combination of 1843U89 with oral folic acid.

Topics: Animals; Body Weight; Dogs; Dose-Response Relationship, Drug; Enzyme Inhibitors; Folic Acid; Humans; Indoles; Intestinal Diseases; Isoindoles; Leucovorin; Mice; Neoplasms, Experimental; Osteosarcoma; Quinazolines; Thymidylate Synthase; Tumor Cells, Cultured

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding

Topics: Alanine Transaminase; Analysis of Variance; Animals; Anti-Arrhythmia Agents; Antidotes; Aspartate Aminotransferases; Body Weight; Bone Marrow; Bone Marrow Cells; Deoxyuridine; Diet; DNA; Eating; Femur; Food Deprivation; Formiminoglutamic Acid; Gas Chromatography-Mass Spectrometry; In Vitro Techniques; Leucovorin; Male; Methylmalonic Acid; Piperidines; Rats; Rats, Sprague-Dawley; Taurine; Vitamin B Complex; Weight Gain

Following p.o. administration to rats bearing advanced colorectal carcinoma, Ftorafur (FT) is converted to 5-fluorouracil (FUra) by microsomal P450 in the liver. To optimize the therapeutic selectivity of the FUra generated from FT, three approaches were utilized: (a) inhibition of FUra degradation to dihydrofluorouracil by uracil as an alternative substrate for uracil reductase in the molar ratio of 4 uracil:1 FT (UFT); (b) modulation of drug inhibition of thymidylate synthase by leucovorin (LV); and (c) by increasing the level of FUra incorporation into cellular RNA by N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate transcarbomylase. The maximum tolerated dose (MTD) of FT and UFT, administered 3 times a day for 28 days, was 150 mg/kg/day and 60 mg/kg/day, respectively. The MTDs were not significantly modified by LV (150 or 600 mg/kg/day), administered by the p.o. route with the drugs, or by PALA (100 mg/kg) administered weekly by the i.v. route. The dose-limiting toxicity of FT alone and in combination with the modulators was stomatitis. The severe alopecia observed with FT alone was reduced significantly by uracil. At the MTD, the antitumor activity of UFT was superior to those of FT and FUra alone and in combination with LV and/or PALA. The 3-month sustained complete tumor regression for UFT, FT, and FUra was 38%, 0%, and 13% (for the weekly schedule), respectively. Although uracil, LV, and PALA individually increased the antitumor activity of FT at its MTD, the combination of the three modulators produced the highest therapeutic efficacy in rats bearing advanced colorectal carcinoma, in which 100% of the treated animals achieved complete and sustained tumor regression. The therapeutic efficacy observed with FT modulation could not be achieved with FUra administered by different schedules, each at its MTD alone or in combination with either LV or PALA. In brief, modulation of FT produced greater therapeutic efficacy and selectivity than FUra. Furthermore, the combined use of modulators capable of inhibiting the degradation pathway of FUra and potentiating the effects of the anabolic metabolites action appears to offer the greatest therapeutic potential.

Topics: Animals; Body Weight; Colorectal Neoplasms; Female; Fluorouracil; Leucovorin; Metabolic Clearance Rate; Microsomes, Liver; Prodrugs; Rats; Rats, Inbred F344; Tegafur

Five groups of pregnant Wistar rats (zinc-deficient diet without folate supplementation; folinic acid, folate monoglutamate, folate polyglutamate-supplemented groups receiving zinc-deficient diet; pair-fed groups as controls) were fed from day one of fertilization with a semisynthetic zinc-deficient diet containing 0.2 mg/kg of Zn in the diet for the 4 deficient groups and 100 mg/kg for the pair-fed group. After 20 days, the zinc status (plasma, liver, femoral bone) was significantly decreased in the zinc-deficient groups. The liver and plasma folate levels were lower in the zinc-deficient groups compared to the pair-fed group. Moreover, the folinic acid and the polyglutamate folate supplementations (100 mg/kg diet) did not normalize the folate status of the animals. Only the supplementation with folate monoglutamate led to correct folate levels in the pregnant rats. Nevertheless, no form of folate supplementation prevented fetal growth retardation in any of the zinc-deficient groups. These results indicate that zinc deficiency in pregnant rats decreases folate bioavailability of folinic acid, folate polyglutamates and, to a lesser extent, that of folate monoglutamate. However, no form of folate supplementation (i.e., folate monoglutamate) prevents fetal growth defect and the incidence of malformation in zinc-deficient rats.

Topics: Animals; Body Weight; Embryonic and Fetal Development; Female; Folic Acid; Glutamates; Leucovorin; Pregnancy; Pregnancy Complications; Pteroylpolyglutamic Acids; Rats; Rats, Wistar; Zinc

Old rats had lower plasma concentrations of folates but not of vitamin B12 than young rats. Old rats injected with pharmacological doses of folic acid (5 mg/kg) or folinic acid (2.5 mg/kg) every 2 days for a 32-day period spontaneously alternated above chance levels at the 0-min retention interval whereas old rats injected with placebo did not. Rats injected with folinic acid that had plasma folate concentrations above the median for that group alternated at the 3-min retention interval whereas none of the other subgroups did. These results indicate that supplementation with folinic acid at pharmacological doses may decrease perseverative responding and improve spatial memory in old rats. However, neither vitamin group was improved in motor coordination, grip strength, or spatial learning in a water maze. There was no hyperactivity or loss of body weight following vitamin supplementation.

Topics: Aging; Animals; Body Weight; Cognition; Folic Acid; Learning; Leucovorin; Male; Memory; Motor Activity; Psychomotor Performance; Rats; Rats, Inbred F344; Space Perception

Despite recent advances in chemotherapy, the prognosis of advanced colorectal cancer remains poor. Although the taurine-based nitrosourea tauromustine (TCNU) has demonstrated schedule-dependent synergism with 5-fluorouracil (5-FU) and leucovorin (LV) against a variety of tumors in vitro, its efficacy relative to and in combination with these drugs in vivo remains unknown. To study this, BALB/C mice had C26 tumor implanted subcutaneously five days prior to the following treatment (doses and route of administration being the same in all groups): Group 1--no treatment; Group 2--TCNU (30 mg/kg by gavage); Group 3--LV (100 mg/kg intraperitoneally [IP]) and, one hour later, LV plus 5-FU (100 mg/kg IP); Group 4--LV and, one hour later, LV plus 5-FU and TCNU; and Group 5--TCNU and, on the following day, LV and, one hour later, LV plus 5-FU. All treatments were repeated seven days later. Body weight and tumor weight were measured twice weekly, and survival was noted. Postmortems were performed in all animals, and evidence of primary or secondary tumor was recorded. All surviving animals were sacrificed at 60 days. We found that 1) 87 percent of animals receiving TCNU and 60 percent of animals receiving LV, 5-FU, and TCNU survived to day 60; none of these animals had evidence of tumor when sacrificed; 2) animals in all other groups died by day 34; 3) evidence of metastases was found in five animals in Group 1 and one each in Groups 2 and 5; and 4) administering TCNU 24 hours prior to 5-FU plus LV resulted in death from toxicity in all animals. Thus, while synergism between TCNU and 5-FU plus LV was not seen, the antitumor properties of TCNU are significantly greater than those of conventional chemotherapy.

Topics: Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Colonic Neoplasms; Drug Therapy, Combination; Fluorouracil; Leucovorin; Male; Mice; Mice, Inbred BALB C; Nitrosourea Compounds; Taurine

Male Wistar rats were subjected to colonic resection and randomized to one of four groups: control group (intraperitoneal NaCl, intravenous NaCl); 5-fluorouracil (5-FU) group (intraperitoneal 5-FU, intravenous NaCl); folinic acid group (intraperitoneal NaCl, intravenous folinic acid); and 5-FU-folinic acid group (intraperitoneal 5-FU, intravenous folinic acid). Treatment was started immediately after surgery and continued until the animals were killed at 3 or 7 days. Anastomotic complications (abscesses or dehiscence) occurred in four of 33 animals in the control group, 12 of 36 in the 5-FU group, one of 32 in the folinic acid group and nine of 36 in the 5-FU-folinic acid group. Anastomotic and skin breaking strength did not differ between groups on day 3 but by day 7 were significantly reduced in the 5-FU group. In rats given 5-FU-folinic acid, breaking strength was also reduced, but less so than in the 5-FU group. Breaking strength in animals receiving folinic acid was similar to that in the control group. In this model colonic healing was impaired after intraperitoneal 5-FU administration, but when folinic acid was added no further deterioration occurred.

Topics: Anastomosis, Surgical; Animals; Body Weight; Colon; Fluorouracil; Hydroxyproline; Leucovorin; Leukocyte Count; Male; Peroxidase; Rats; Rats, Inbred Strains; Skin; Time Factors; Wound Healing

Two strategies for modulation of 5-fluorouracil (FUra) activity were compared in vivo in advanced murine CD8F1 breast tumors with regard to three parameters: chemotherapeutic activity, inhibition of thymidylate synthase (TSase) activity, and incorporation of FUra into RNA, (FU)RNA. Inhibition of TSase by FUra was modulated by leucovorin (LV), and the incorporation of FUra into RNA was increased by the administration of otherwise lethal doses of FUra followed by uridine "rescue". Thymidylate synthase activity was inhibited substantially (49%) by low-dose FUra at 25 mg/kg, but was not further enhanced (48%) by repeated daily treatments at the same dose (FUra25 x 4). Inhibition of TSase was somewhat enhanced (55%) by the addition of LV to FUra25 x 4, and a greater therapeutic effect was obtained with FUra25 x 4 + LV over FUra25 x 4 alone. FUra as a single agent at the maximum tolerated weekly dose of 100 mg/kg inhibited TSase activity 66-73%. This inhibition was further enhanced slightly by the addition of LV (71-82%), and its therapeutic efficacy was greater than with FUra25 x 4 with or without LV. However, in contrast to low dose FUra25 x 4, the antitumor effect of FUra100 was not enhanced by LV. (FU)RNA increased with FUra dose from 0.4 (FUra25) to 2.2 nmol/mg DNA (FUra100). At a very-high-dose of FUra (200-225 mg/kg) followed by uridine "rescue", TSase inhibition was not further enhanced, but both (FU)RNA (4.8 nmol/mg DNA) and the therapeutic efficacy were increased. Since TSase could not be further inhibited at doses above FUra100, the increased chemotherapeutic efficacy correlated with increased (FU)RNA.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Dose-Response Relationship, Drug; Fluorouracil; Leucovorin; Mammary Neoplasms, Experimental; Mice; RNA; Thymidylate Synthase; Time Factors; Uridine

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Body Weight; Drug Synergism; Leucovorin; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Tegafur; Tumor Cells, Cultured; Uracil; Urinary Bladder Neoplasms

The administration of chemotherapy in clinical situations is limited frequently because of the associated toxicity to normal bone marrow cells, gastrointestinal epithelium, and other host tissues. Although nutritional support has been advocated to reduce chemotherapy-related toxicity in cancer patients, few studies substantiate this clinical impression. The current study was performed to determine the role of nutritional status and enteral nutrient intake as determinants of methotrexate (MTX) toxicity in a well-controlled, tumor-bearing animal model. After subcutaneous mammary tumor (AC-33) inoculation, 56 female Lewis/Wistar rats were assigned randomly to one of the following two nutritional regimens for 14 days: (1) protein-depleted chow (PC) (0.03% protein; 4.27 kcal/g) or (2) standard chow (RC) (22.0% protein; 3.50 kcal/g). After 7 days of dietary control, all animals received one of three weight-adjusted doses of MTX (5, 10, or 20 mg/kg intramuscularly [IM] ) or placebo. All animals received leucovorin rescue (0.6 mg IM) at 6 and 24 hours after MTX injection. Improved nutritional status was associated with a significant reduction in objective measures of MTX-related morbidity and mortality. At low doses of MTX (5 and 10 mg/kg), the mean duration of clinical signs of toxicity (i.e., hair loss, lethargy, and diarrhea) and severity of leukopenia were greater in protein-depleted (PD) animals. With high-dose MTX (20 mg/kg), mortality was increased significantly in PD animals (100%) compared with well-nourished animals (0%). Equivalent tumor response was observed in PD and well-nourished animals. Thus, improved nutritional status by enteral nutrition reduced the morbidity and mortality associated with MTX significantly in this tumor-bearing animal model.

Topics: Adenocarcinoma; Animals; Body Weight; Dietary Proteins; Enteral Nutrition; Female; Leucovorin; Methotrexate; Protein Deficiency; Rats; Rats, Inbred Lew; Rats, Inbred Strains

One hundred consecutive patients with previously untreated advanced squamous cell carcinoma of the head and neck were treated with induction combination chemotherapy followed by definitive surgery and/or radiotherapy, and were evaluated for radiotherapy related toxicity. The induction regimen consisted of cisplatin, bleomycin and methotrexate/leucovorin. Acute toxicity consisted predominantly of mucositis and weight loss, and was mild or moderate by degree in 94% of patients. Six percent of patients experienced severe or life threatening acute toxicities. Two acute toxic deaths were noted in this series, one from a combination of mucositis, weight loss and infection and one from hypoglycemia of unknown origin. Thirty-five percent of patients had radiation treatment interrupted briefly because of acute toxicity. Toxicity was greatest in patients who were nonresponders to induction chemotherapy and such may have been related to the continued presence of advanced tumor. Radiotherapy dose, surgical intervention and age did not have an impact on the presence or degree of acute toxicity. Late toxicities included: hypothyroidism in 32% of patients tested: osteoradionecrosis in 5% of patients, associated primarily with a composite resection (4 of 5 cases); and soft tissue ulcerations in 3%. Taken together, these data indicate that induction combination chemotherapy did not significantly increase the toxicity of subsequent radiotherapy with or without surgery.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Body Weight; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Hypothyroidism; Leucovorin; Male; Methotrexate; Mucous Membrane; Osteoradionecrosis; Pneumonia; Radiotherapy; Time Factors; Ulcer

Topics: Abdomen; Animals; Bleomycin; Body Weight; Drug Administration Schedule; Female; Fluorouracil; Injections, Intraperitoneal; Leucovorin; Methotrexate; Postoperative Period; Rats; Rats, Inbred Strains; Stomach; Vincristine; Wound Healing

Topics: Animals; Blood Cell Count; Body Weight; Dogs; Folic Acid; Folic Acid Antagonists; Leucovorin; Triazines

Topics: Animal Nutritional Physiological Phenomena; Animals; Body Weight; Fatty Acids, Unsaturated; Feces; Female; Folic Acid; Hemoglobins; Intestinal Absorption; Intestine, Small; Leucovorin; Leukocyte Count; Linoleic Acids; Lipid Metabolism; Malabsorption Syndromes; Organ Size; Oxidation-Reduction; Peroxides; Rats; Reticulocytes; Tetrahydrofolates

1. Methods are described for the extraction, separation by ion-exchange chromatography and estimation by microbiological assay of the folates in sheep liver. 2. Injection of [2-(14)C]-pteroylglutamate into a sheep fed on a stock diet led to extensive labelling of chromatographically separable liver folates. About 12% of the label in the liver could not be extracted by the method used. 3. Liver folates were examined in five ewes fed on restricted amounts of a diet of wheaten hay-chaff and gluten and injected weekly with vitamin B(12). Chromatographic separation was followed by microbiological assay with Lactobacillus casei, Streptococcus faecalis R. and Pediococcus cerevisiae both before and after treatment of fractions with conjugase (gamma-glutamylcarboxypeptidase). Evidence was obtained that the folates present were predominantly polyglutamate forms of tetrahydropteroylglutamate, 5-methyltetrahydropteroylglutamate and 5- (and 10-) formyltetrahydropteroylglutamates. Differences in the responses of the assay organisms permitted quantitative distinction between these three main classes of folates. 4. Methyltetrahydrofolates were eluted in seven successive peaks that were separated by constant increments in the logarithm of eluant [P(i)]. A similar relationship existed for seven successive peaks of tetrahydrofolate and may also have existed for each of the two series of formyltetrahydrofolates. 5. Based on these and other observations it is proposed that sheep liver folates consist predominantly of the mono- to hepta-glutamates of each of the reduced pteroates identified. The methods employed allowed quantitative determinations to be made of most of the folates present. The predominant forms were hexaglutamates. 6. Four components active for L. casei were detected that could not be identified. Three of them were polyglutamates.

Topics: Animal Feed; Animals; Body Weight; Carboxypeptidases; Chromatography, Ion Exchange; Enterococcus faecalis; Female; Folic Acid; Glutamates; Glutens; Kidney; Lactobacillus; Leucovorin; Liver; Pediococcus; Radioisotopes; Sheep; Swine; Tetrahydrofolates; Triticum; Vitamin B 12

1. Metabolism of folate was studied in six ewes in an advanced state of vitamin B(12) deficiency as judged by voluntary food intake and in their pair-fed controls receiving vitamin B(12). A group of four animals that were maintained throughout the experiment at pasture was also studied. 2. After 34-40 weeks on the cobalt-deficient diet urinary excretion of formiminoglutamate by four deficient animals was about 3.2mmol/day and this was not significantly decreased by injection of three of them with about 4.5mug of [2-(14)C]folate/kg body weight per day for 5 days. Three days after the last injection retention of [2-(14)C]folate by the livers of the deficient animals (5.5% of the dose) was lower than that of their pair-fed controls (26% of the dose) but there was no evidence of net retention of injected folate in the livers of either group. Urinary excretion of (14)C indicated that renal clearance of folate may have been impaired in very severe vitamin B(12) deficiency. 3. As estimated by microbiological assays total folates in the livers of animals at pasture (12.9mug/g) included about 24% of 5-methyltetrahydrofolate as compared with about 72% of a total of 12.5mug/g in three further ewes fed on a stock diet of wheaten hay-chaff and lucerne-chaff. Liver folates of vitamin B(12)-deficient animals (0.5mug/g) included about 88% of 5-methyltetrahydrofolate as compared with about 51% of a total of 5.2mug/g in pair-fed animals treated with vitamin B(12). 4. Chromatography of liver folates of the pair-fed animals permitted quantitative estimates of the pteroylglutamates present. The results showed that the vitamin B(12)-deficient livers were more severely depleted of tetrahydrofolates and formyltetrahydrofolates than of methyltetrahydrofolates and that as the deficiency developed they were more severely depleted of the higher polyglutamates than of the monoglutamate within each of these classes. Results from animals injected with [2-(14)C]folate indicated an impairment of the exchange between pteroylmonoglutamates and pteroylpolyglutamates in the livers of deficient animals. 5. In vitamin B(12)-deficient animals with food intakes below 200g/day some of the liver folates were not completely reduced and some degradation of pteroylpolyglutamates was detected. The latter condition may have been associated with fatty liver. 6. The results are discussed in relation to current theories of vitamin B(12)-folate interactions.

Topics: Animals; Azo Compounds; Biological Assay; Body Weight; Carbon Radioisotopes; Chromatography; Cobalt; Enterococcus faecalis; Feces; Folic Acid; Glutarates; Lactobacillus; Leucovorin; Liver; Pediococcus; Sheep; Tetrahydrofolates; Vitamin B 12 Deficiency

Topics: Adrenergic beta-Antagonists; Animals; Antimalarials; Blood Pressure; Body Weight; Cardiac Output; Dogs; Female; Heart; Heart Rate; Lethal Dose 50; Leucovorin; Lung; Male; Mice; Mortality; Pneumoencephalography; Proguanil; Rats; Reserpine; Reticulocytes; Species Specificity; Triazines

Topics: Aminopterin; Animals; Antineoplastic Agents; Body Weight; Dosage Forms; Folic Acid Antagonists; Leucovorin; Leukemia, Experimental; Male; Methotrexate; Mice; Quinazolines

Topics: Animals; Blood Chemical Analysis; Body Weight; Dogs; Drug Combinations; Female; Folic Acid; Hemodynamics; Leucovorin; Male; Organ Size; Poisoning; Pyrimethamine

Topics: Body Weight; Choline; Dietary Fats; Folic Acid; Leucovorin; Lipotropic Agents; Liver; Organ Size; Pharmacology; Rats; Research; Vitamin B 12; Vitamin B Complex; Vitamins

Topics: Animals; Antibody Formation; Body Weight; Immunosuppressive Agents; Injections, Intraperitoneal; Leucovorin; Methotrexate; Mice; Mortality; Pharmacology; Research; Typhoid-Paratyphoid Vaccines