Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diethyldithiocarbamate (DDTC) has been shown to inhibit nephrotoxicity induced by cis-platinum (DDP) without inhibition of tumor response in the rat. We report here that DDTC at doses of 25-300 mg/kg inhibits DDP-induced nephrotoxicity and bone marrow toxicity in C57BL/6 X DBA/2F1 (hereafter called B6D2F1) mice, F344 rats, and beagle dogs and is also antiemetic in the dog. DDTC doses which afford excellent protection do not decrease median survival time following DDP treatment in L1210 and P388 leukemias, B16 melanoma, and Lewis lung and colon 26 carcinomas in B6D2F1 mice when DDTC is given 2 h after DDP. Preliminary experiments indicate that DDTC does not alter median survival time after treatment of P388 leukemia with the platinum analogues diammine(1,1-cyclobutanedicarboxylato)platinum(II) and cis-diisopropylamine-cis-dichloro-trans-dihydroxyplatinum(IV ). Maximum blood urea nitrogen levels after DDP treatment are reduced significantly by DDTC in all species; blood urea nitrogen elevation, total kidney platinum, weight loss, and leukopenia correlate with DDP-DDTC interval in the rat and indicate optimum protection at 2 h, the shortest interval examined. Bone marrow toxicity was assessed by peripheral white blood cell counts in all species and by marrow cellularity in the mouse. White blood cell nadirs were higher and bone marrow recovered more rapidly after DDTC compared with DDP given alone. DDP reduced marrow cellularity 50-60% in the mouse; administration of DDTC 2 h after DDP afforded no protection to the lymphocytes in the marrow but maintained the granulocyte + precursor population near control levels. DDTC plasma pharmacokinetic values have been determined after s.c., i.p., and i.v. administration in the mouse, rat, and dog. Peak plasma levels of 0.3-1.2 mM are observed after a 250-mg/kg dose, with a plasma half-life of 10-20 min. Our data indicate that DDTC may provide protection against most clinically significant toxicities arising from cis-platinum at doses which do not inhibit tumor response.
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PMID:Selective protection against cis-diamminedichloroplatinum(II)-induced toxicity in kidney, gut, and bone marrow by diethyldithiocarbamate. 300

A few 1-aryl 3-(2-chloroethyl)ureas (CEU) were synthesized and screened in vitro for their cytotoxicity. Some of these derivatives were assayed for their mutagenicity, their in vivo toxicity and their antineoplastic activity. Methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tertbutyl (3-(2-chloroethyl) ureido) phenyl) butyrate, 4-methyl and 4-tert-butyl (3-(2-chloroethyl) ureido) benzene had an ID50 of 28, 20 and 4 microM respectively when tested on LoVo cells, while chlorambucil (CBL) and CCNU had an ID50 of 21 and 45 microM. These 3 chloroethyl urea derivatives were not toxic when injected i.p. at doses up to 220 mg/kg, whereas chlorambucil was already toxic at 18.5 mg/kg. The survival time of BDF1 mice bearing L1210 leukemia tumors was significantly enhanced by intraperitoneal injections of CBL and CEU. The most cytotoxic derivative (tert-butyl derivative) gave the best antineoplastic activity with a median survival time 1.77 times that of the control at 10 mg/kg/day and was not toxic, whereas CBL at this concentration enhanced survival time by a factor of 1.6 and presented important side effects. The 4-tert-butyl (3-(2-chloroethyl) ureido) benzene and the methyl 4-(p-(3-(2-chloroethyl) ureido) phenyl) butyrate showed no mutagenicity when assayed on TA-97, TA-98, TA-100 and TA-102, four strains of S. thyphimurium, while CBL had a weak effect on TA-102 and CCNU was highly mutagenic on TA-100 and TA-102.
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PMID:In vitro and in vivo activity of 1-aryl-3-(2-chloroethyl) urea derivatives as new antineoplastic agents. 305 47

The study investigates clinical nutrition of oncological patients as an essential adjuvant component in the whole therapeutical concept. The main subject of the study was the transfer of nutritional concepts which were developed in non-malignant diseases to oncological patients. We defined the homeostasis of patients by biochemical and biophysical parameters in blood (osmolality, Na, K, total protein, albumin, triglycerides, NEFA, glucose, lactate, creatinine, urea, total nitrogen, amino acids) and urine (volume, osmolality, Na, K, creatinine, urea, total nitrogen, and amino acids). Of special interest was the homeostasis of nitrogen, which was characterized by the loss of nitrogen and nitrogen balances. 10 patients with either transplantable panmyeolopathy or leukemia were investigated including a phase of immunsupressive treatment by total body radiation and cytostatic treatment. Parenteral nutrition was made with amino acids (1 g/kg/d), carbohydrates (6.5 g/kg/d) and fat (1 g/kg/d). During the preparatory phase nutrition was interrupted for two consecutive days because high amounts of electrolyte solution with up to 6 1/day were needed to protect the kidney. The period of investigation covered the complete period of treatment which endured up to three months. The essential result was the achievement of a constant body weight which decreased drastically under the conventional treatment without optimized nutrition. The homeostasis remained unchanged inspite of the fact that great changes occurred individually. Nitrogen balance and nitrogen loss demonstrate the strong influence of immun-suppresive treatment with N-losses of up to 20 g per day.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Adjuvant parenteral nutrition in chemo- and radiotherapeutic measures in hematology]. 309

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.
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PMID:Effects of fosfomycin, mesna, and sodium thiosulfate on the toxicity and antitumor activity of cisplatin. 314 27

The authors used isotopic infusions of 6-3H-glucose, U-14C-glucose, and 14C-urea and calorimetry to investigate energy expenditure and metabolic profiles in 19 patients with hematologic malignancy. The average age of these patients was 62 years. Eleven patients had either leukemia or myeloproliferative disorders (LEMP). The rest had lymphoma (LYMPH). The Resting Energy Expenditure (REE) in the LYMPH patients was 1015 +/- 115 kcal/24 hr. This value in the LEMP group was significantly elevated at 2083 +/- 270 kcal/24 hr (P less than 0.025) despite similar weights and ages between the two groups. Net Protein Catabolism (NPC) in the LYMPH group was 82 +/- 29 mg/kg.hr. In contrast the value in the LEMP group was more than doubled at 174 +/- 30 mg/kg.hr (P less than 0.05). Glucose production in the LYMPH group was 14.1 +/- 2.7 mumol/kg.min, and the percent of glucose uptake oxidized in the LYMPH group was 37% +/- 9%. In contrast, glucose production in the LEMP group was significantly elevated (P less than 0.025) at 41.0 +/- 8.1 mumol/kg.min, and the percent of glucose uptake oxidized was significantly depressed (P less than 0.05) at 20% +/- 4% compared with the value in the LYMPH group. Glucose recycling in the LYMPH group was 9.0% +/- 6%. In the LEMP group the rate of recycling was significantly elevated at 60.3% +/- 4.8% (P less than 0.005). The percent suppression of endogenous glucose turnover during glucose infusion in the LYMPH group was 96% +/- 4%. The value for the LEMP patients was significantly less at 30.2% +/- 5% (P less than 0.0005). The serum cortisol concentration in the LYMPH patients was 285 +/- 74 nmol/l. The value in the LEMP patients was significantly higher (P less than 0.005) at 579 +/- 22 nmol/l. The authors concluded that hematologic malignancy is not a homogeneous group when evaluated metabolically. Lymphoma patients are similar metabolically to normal volunteers, but LEMP patients form a distinct group with major abnormalities in both glucose and protein kinetics and energy expenditure.
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PMID:Metabolism in hematologic malignancy. 316 75

Investigations on the in vivo interaction of nicotine and antineoplastic agents were prompted by the observation that nicotine lowered the carcinogenicity of the alkylating agent methylnitrosourea (MNU) in rats. Since alkylating agents play an important role as antitumor drugs, nicotine may influence the anticancer activity of anticancer drugs, especially alkylating agents. Two tumor models were selected: (a) autochthonous, MNU-induced mammary carcinoma and (b) transplanted rat leukemia L5222. The antitumor drugs investigated were cyclophosphamide (CPA) and 1-(2-chloroethyl)-1-nitroso-3-(2-hydroxyethyl) urea (HECNU). Nicotine was administered continuously by Alzet-osmotic minipumps, at a dose of 2.5 and 5 mg/kg daily. Under these conditions the observed nicotine and cotinine plasma levels approximated levels measured in heavy smokers (nicotine peak level, 47 ng/ml; cotinine peak level, 635 ng/ml). In MNU-induced autochthonous mammary carcinoma, a solid hormone-dependent tumor, the combination of HECNU and nicotine yielded greater tumor inhibition than HECNU alone. The anticancer activity of CPA on transplanted L5222-leukemia, on the other hand, was decreased by continuous infusion of nicotine. The interpretation of both results has to take into account the following possibilities of nicotine action: influence on (a) microcirculation, (b) cell proliferation, (c) membrane transport, (d) metabolism of cytotoxic drugs, and (e) hormonal milieu. The results demonstrate that nicotine is able to influence the outcome of antitumor treatment. The mechanism of interaction needs clarification. Additionally, further combination studies with other classes of cytotoxic drugs are warranted.
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PMID:Interaction of nicotine with anticancer treatment. 318 71

Proton NMR longitudinal relaxation times (T1; 10.7 MHz; 37 degrees C) were measured in the kidneys and blood serum of mice inoculated with P388 leukemia, and/or treated with the chemotherapeutic drug cis-diamminedichloroplatinum(II) (cis-Pt). In parallel, serum total protein content, urea and creatinine levels were determined and protein fractions were separated electrophoretically. Serum T1 was found to be 1518 +/- 73 ms (1 SD) in control mice, 1670 +/- 69 ms in leukemic mice, and 1380 +/- 71 ms in the healthy and the leukemic cis-Pt treated mice. The T1 increase in leukemic serum and T1 decrease in the serum of cis-Pt injected mice are attributed to decreased and increased protein contents respectively. A detailed analysis in terms of electrophoretic fractions of serum proteins reveals that the serum relaxation rate 1/T1 is a multilinear function of the mass concentrations of the main serum protein fractions, explaining all serum T1 effects. This makes T1 a non-specific blood parameter. The kidney T1 was found to be 311 +/- 12 ms in normal mice and 334 +/- 20 ms in leukemic mice. A dramatic T1 increase is observed when the mice are injected with cis-Pt; the values are 400 +/- 38 ms and 407 +/- 39 ms for healthy and leukemic mice, respectively. This effect is related to the nephrotoxicity of the drug, as evidenced by serum urea and creatinine levels and protein content being higher than normal.
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PMID:The relationship between serum water proton T1 and protein content in the P388 leukemic mouse and the effect of chemotherapy by cis-diamminedichloroplatinum(II). 327 29

A sex difference in nitrogen balance was investigated in 40 adults, 21 men and 19 women, undergoing chemoradiotherapy and marrow transplantation for leukemia and receiving total parenteral nutrition. Twenty-four hour collections of urine and mixed urine-stool were analyzed for total nitrogen daily through day 14 posttransplant. Nitrogen balance, corrected for changes in blood urea nitrogen, decreased significantly over time (p less than 0.005) in both men and women, but men experienced a greater negative nitrogen balance during the time period (p less than 0.001). Mean daily nitrogen balance in men was -6.0 g for week 1 and -9.2 g for week 2, corresponding to -3.3 g and -5.6 g in women for week 1 (p less than 0.005) and 2 (p less than 0.01), respectively. The differences remained after controlling for stress level and adjusting for total calorie intakes. There were no differences in age, disease status, or nitrogen intakes per kg ideal body weight, and no effects on nitrogen balance by arm muscle area at admission, cyclosporine use, or the branched-chain amino acid content of the parenteral solution. The average rise in 3-methylhistidine excretion was 23% in men and 11% in women. These results suggest higher per kg nutrient needs in males during stress and may indicate differing metabolic responses to stress. The possibility of gender differences should be considered in research evaluating nitrogen metabolism during severe stress.
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PMID:Sex differences in nitrogen balance following marrow grafting for leukemia. 329 77

Human interferons have been shown to be effective treatment for hairy cell leukaemia and are now commercially available. Their role in treatment of solid tumours has yet to be established. This study assessed the value of alpha 2 interferon (IFN) in an experimental breast cancer model. Four groups of female Sprague-Dawley rats were studied. The first received three intravenous injections (7 mg/kg) of N-nitroso-methyl urea (NMU) at weeks 0, 3 and 7. The second received the same NMU dosage regime plus IFN (100,000 IU, twice weekly for 3 weeks). A third received IFN alone and the fourth was a control group receiving three intravenous injections of normal saline. At week 16, 19 of 20 rats in the NMU alone group had developed tumours significantly more than four of 15 rats with tumour in the NMU plus IFN group (P less than 0.001). Both the mean tumour number/rat and the mean tumour weight/rat was significantly more in the NMU group than the NMU plus IFN group P less than 0.05). No rats in the IFN alone or control group developed tumour. These data suggest that IFN prevents carcinogen induced breast cancer in rats. It may have a role in the prevention and treatment of human breast cancer.
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PMID:Alpha 2 interferon in the prevention of N-nitroso-methyl urea induced breast cancer in rats. 337 77

3'-Deamino-3'-(4-morpholinyl)adriamycin (MRA) and 3'-deamino-3'(3-cyano-4-morpholinyl)adriamycin (MRA-CN) were compared with adriamycin (ADR) in ADR-sensitive (P388/S) and -resistant (P388/ADR) murine leukemia cell lines with respect to cytotoxicity and cellular accumulation. MRA is only two- to threefold more cytotoxic to P388/S in culture than ADR, whereas MRA-CN is 500-fold more cytotoxic than ADR to this cell line. Yet both MRA and MRA-CN retain their potency against P388/ADR in spite of a 150-fold decrease in potency for ADR. The observed noncross-resistance of both MRA and MRA-CN in P388/ADR correlates with their increased cellular uptake and retention relative to ADR and the inability of P388/ADR to exclude these analogs as readily as it does ADR. The decreased uptake of MRA and MRA-CN in P388/ADR relative to P388/S (1.5 to 2.0-fold), the increased efflux, and the ability of verapamil to enhance cellular uptake of these analogs in P388/ADR, as it does with ADR, all indicate that the mechanism of ADR-resistance effects ADR and the morpholino analogs in a similar manner but to far different extents. The potent cytotoxicity of MRA-CN appears to be related to strong cellular interactions of the drug with macromolecules that are characterized by its nonextraction from cells by chloroform: methanol or 10 M urea and may therefore represent covalent binding.
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PMID:Uptake and retention of morpholinyl anthracyclines by adriamycin-sensitive and -resistant P388 cells. 345 46


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