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At least 163 records · Page 9Linked to original sources
PubMed1979

Antitumor activity of 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) and 1-(2-chloroethyl)-3-(4-methyl-cyclohexyl)-1-nitrosourea (MeCCNU) on Yoshida sarcoma ascites cells implanted into the colon wall of rats.

Three thousand Yoshida sarcoma cells were inoculated into the wall of the descending colon of each of 120 male Sprague-Dawley rats. On day 8 after the tumor implantation, the animals were at random divided into four groups of 30 rats each. The effect of cyclophosphamide (70 mg/kg), BCNU (25 mg/kg), and methyl-CCNU (45 mg/kg) after single i.p. application was investigated. The Yoshida sarcoma transplanted into the colon is sensitive to all three chemotherapeutic drugs. At the doses given cyclophosphamide showed the best results. The two nitrosoureas had a comparable antitumor activity but methyl-CCNU showed a more distinct toxic effect. The introduction of this model for testing new cytostatics in animal experiments is discussed.

Animals↗
PubMed1982

The assessment of response of murine transplantable colon tumors to combination chemotherapy.

The mouse adenocarcinoma of the colon (MAC) system, which has been shown to be a good model for human colorectal carcinoma in terms of its chemosensitivity, was tested with two modified human protocols (MeCCNU + 5 FU, BCNU + 5 FU) in an attempt to evaluate its suitability as a model for developing new regimens of combination chemotherapy for treating patients with colorectal carcinoma. This attempted evaluation raised problems regarding, firstly, the length of time available before tumours became too large in control and non-responding hosts to maintain adequate mobility and, secondly the assessment of response to the drugs. The commencement of drug administration 3 days after transplantation and the assessment of response by measuring delay in time for tumor growth to reach a given volume, with the results analysed by Gehan's (generalised Wilcoxon) test, gave a workable method of evaluation. This method is presented as being suitable for use in the study of transplantable solid tumor lines as models for combination chemotherapy.

Adenocarcinoma↗
PubMed1979

Examination of four newly synthesized 2-chloroethylnitrosoureas in comparison with BCNU, CCNU, MeCCNU, chlorozotocin and hydroxyethyl-CNU in preterminal rat leukemia L 5222.

The newly synthesized nitrosoureas 1-(2-chloroethyl)-1-nitroso-3-(methylenecarboxamido)-urea (Acetamido-CNU), 1-(2-chloroethyl)-1-nitroso-3-(4-morpholino)-urea (Morpholino-CNU), 1-(2-chloroethyl)-1-nitroso-3-(1-piperidino)-urea (Piperidino-CNU), and 2-[3-(2-chloroethyl)-3-nitrosoureido]-ethylmethanesulfonate (Ethylmethanesulfonato-CNU) were compared in their chemotherapeutic activity against preterminal rat leukemia L 5222 with BCNU, CCNU, MeCCNU, Chlorozotocin, and Hydroxyethyl-CNU. With respect to the dose range effecting a median survival time of more than 90 days, MeCCNU was superior to the other substances. Chlorozotocin, on the other hand, was the only substance which achieved no cures in this experimental arrangement. From the four newly introduced substances the water-soluble substances Acetamido-CNU and Morpholino-CNU were approximately comparable to CCNU with regard to the dose range effecting a median survival time of greater than 90 days. Piperidino-CNU and Ethylmethanesulfonato-CNU also effected cures; however, only Piperidino-CNU in one dosage effected a median survival time of greater than 90 days.

Animals↗
PubMed1985

Effect of nitrosoureas on calmodulin activity in vitro and in mouse intestine in vivo.

The effects of BCNU, CCNU, methyl-CCNU, streptozotocin, and chlorozotocin on calmodulin activity were studied in vitro and in vivo. Preincubation of BCNU, CCNU, and methyl-CCNU with calmodulin produced a concentration-dependent inhibition of in vitro calmodulin activity expressed as stimulation of cyclic nucleotide phosphodiesterase. Cyclohexylisocyanate produced a similar inhibition. Streptozotocin and chlorozotocin had no effect. Calmodulin inhibition by methyl-CCNU was dependent on the concentration of calcium in the preincubation mixture. Administration of methyl-CCNU or chlorozotocin IP to CF1 mice produced a dose-dependent inhibition of calmodulin activity in the small intestine. Methyl-CCNU produced a significant decrease in intestinal calmodulin activity as early as 1 h after treatment, an effect that persisted up to 52 h. Morphologic changes in the intestinal crypt epithelial cells were evident between 27 h and 5 days after treatment, but not earlier than 27 h. Renal and testicular calmodulin activity and morphology were unaffected. Although it was not possible to correlate the extent of calmodulin inhibition with severity of the intestinal lesions, the data suggested a relationship between reduced activity of calmodulin in a tissue and the ultimate appearance of lesions. This apparent interaction between an antitumor drug and calmodulin in vivo could have multiple implications for cancer chemotherapy.

Animals↗
PubMed1985

Differential distribution and covalent binding of two labeled forms of methyl-CCNU in the Fischer 344 rat.

The present study compares the organ distribution and covalent binding of MeCCNU labeled either within the carbamylating [( cyclohexyl-1-14C]MeCCNU; Chx-14C-MeCCNU) or alkylating [( 2-chloroethyl-1,2-14C]MeCCNU; Cle-14C-MeCCNU) region of the compound in an animal model shown to be suitable for studying the nephrotoxicity of the nitrosoureas. Extraction of tissue homogenates with organic solvents of increasing polarity, and subsequent analysis of these extracts by HPLC showed fat to accumulate the highest concentration of parent compound. Kidney accumulated the highest levels of the more polar ether- and methanol-extractable metabolites and/or degradation products of either cyclohexyl-derived or chloroethyl-derived 14C-MeCCNU. Striking differences were apparent in the accumulation, degradation and/or metabolism, and tissue distribution of covalently bound radioactivity for the chloroethyl and cyclohexyl moieties. For example, approximately twice as much cyclohexyl-derived 14C was bound covalently to protein of kidney than to protein of liver or lung. In contrast, approximately twice as much chloroethyl-derived 14C was bound to lung protein than to liver of kidney protein. No radioactivity was bound covalently to tissue DNA following Chx-14C-MeCCNU administration. On the other hand, at 4 h, chloroethyl-derived 14C was irreversibly bound to DNA in the relative amounts of kidney (5.0 nmol/mg), liver (2.7 nmol/mg), and lung (1.25 nmol/mg). These results demonstrate that MeCCNU metabolites and/or degradation products are preferentially accumulated in kidney, a primary target organ for MeCCNU toxicity. Moreover, kidney protein and DNA were subject to extensive carbamylation and alkylation reactions as measured by irreversibly bound cyclohexyl-derived and chloroethyl-derived 14C, respectively. These data suggest that the extent of irreversibly bound drug to tissue macromolecules may be a valid predictor of MeCCNU toxicity. However, the relative toxicological significance of either protein carbamylation or DNA alkylation in mediating MeCCNU-induced nephropathy is not yet understood.

Adipose Tissue↗
PubMed1986

Chemical cholecystitis after intrahepatic chemotherapy. The case for prophylactic cholecystectomy during pump placement.

Recent repopularization of intrahepatic infusion chemotherapy has been made possible by the development of the implantable Infusaid pump. Surgical placement of a catheter into the gastroduodenal artery with division of collaterals to the stomach, duodenum, and pancreas has reduced the incidence of gastroduodenal ulceration and pancreatitis. The risk of chemical cholecystitis similarly demands prevention. Anatomically, the cystic artery is a branch of the right hepatic artery in over 95 percent of patients. As a result, even a normal gallbladder is subjected to high-dose chemotherapy with the risk of development of drug-induced cholecystitis. In our first six patients undergoing pump implantation who had normal appearing gallbladders at the time of surgery, two developed symptomatic cholecystitis, necessitating cholecystectomy after receiving intrahepatic chemotherapy. As a result, we recommend elective cholecystectomy at the time of arterial catheterization for intrahepatic chemotherapy.

Adult↗
PubMed1978

Chemotherapy for squamous carcinoma of the cervix: doxorubicin--methyl CCNU.

Treatment was initiated for metastatic or recurrent squamous carcinoma of the cervix with a combination of doxorubicin and methyl CCNU in 37 patients. Results after at least one full course of chemotherapy were fully evaluated in 31 of these patients. The objective response rate of 45.1 per cent obtained with this therapy compared favorably with those obtained by other authors using single or multiple agents. This chemotherapy regimen may need to be modified to improve patients' tolerance. The improved survival rate and high number of complete remissions demonstrated in this pilot study show promise for this type of chemotherapy in the future.

Adult↗
PubMed1984

Stereoselective monooxygenation of carcinostatic 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea by purified cytochrome P-450 isozymes.

Three highly purified forms of liver microsomal cytochrome P-450 (P-450a, P-450b and P-450c) from Aroclor 1254-treated rats catalyzed 1-(2-chloroethyl)-3-(cyclohexyl)-1-nitrosourea (CCNU) and 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) monooxygenation in the presence of purified NADPH-cytochrome P-450 reductase, NADPH, and lipid. Differences in the regioselectivity of CCNU and MeCCNU monohydroxylation reactions by the cytochrome P-450 isozymes were observed. Cytochrome P-450-dependent monooxygenation of CCNU gave only alicyclic hydroxylation products, but monooxygenation of MeCCNU gave alicyclic hydroxylation products, an alpha-hydroxylation product on the 2-chloroethyl moiety, and a trans-4-hydroxymethyl product. A high degree of stereoselectivity for hydroxylation of CCNU and MeCCNU at the cis-4 position of the cyclohexyl ring was demonstrated. All three cytochrome P-450 isozymes were stereoselective in primarily forming the metabolite cis-4-hydroxy-trans-4-Methyl-CCNU from MeCCNU. The principal metabolite of CCNU which resulted from cytochromes P-450a and P-450b catalysis was cis-4-hydroxy CCNU, whereas the principal metabolites from cytochrome P-450c catalysis were the trans-3-hydroxy and the cis-4-hydroxy isomers. Total amounts of CCNU and MeCCNU hydroxylation with cytochrome P-450b were twice that with hepatic microsomes from Aroclor 1254-treated rats. Catalysis with cytochromes P-450a and P-450c was substantially less effective than that observed with either cytochrome P-450b or hepatic microsomes from Aroclor 1254-treated rats.

Animals↗
PubMed1989

Cytochrome P-450-dependent formation of alkylating metabolites of the 2-chloroethylnitrosoureas MeCCNU and CCNU.

Rat liver microsomes catalyzed the biotransformation of the clinically important nitrosourea anticancer agents 1-(2-chloroethyl)-3-(trans-4-methyl-cyclohexyl)-1-nitrosourea (MeCCNU) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) to alkylating metabolites that bound covalently to microsomal protein and to DNA. The enzyme-mediated microsomal alkylation required NADPH and oxygen and was inhibited by carbon monoxide, indicating the participation of a cytochrome P-450-dependent monooxygenase. Additional studies with inhibitors such as piperonyl butoxide and with the inducers 3-methylcholanthrene and phenobarbital were consistent with this view. In contrast to these observations on the formation of alkylating metabolites, carbamylation reactions were not affected significantly by microsomal metabolism. Reduced glutathione, cysteine or N-acetylcysteine decreased the microsomal alkylation by MeCCNU and produced a corresponding increase in the formation of polar metabolites that was resolved by HPLC as three distinct N-acetylcysteine-MeCCNU adducts. The addition of semicarbazide to the reaction decreased microsomal alkylation by 30%, indicating that the formation of the alkylating species may proceed via an aldehyde intermediate. Renal microsomes were not found to catalyze the alkylation reaction. Moreover, MeCCNU inhibited the renal slice accumulation of p-aminohippuric acid only in the presence of liver microsomes and NADPH, suggesting that a liver metabolite may be responsible for the renal toxicity of the parent nitrosourea.

Acetylcysteine↗
PubMed1990

Base sequence specificity of three 2-chloroethylnitrosoureas.

Chemical modifications of guanine are some of the most common results of interactions of DNA with many carcinogens and anti-cancer drugs, including nitrosoureas, nitrogen mustards, triazenes, polycyclic aromatics, and aflatoxins. The base sequence specificity for alkylation of guanines by three 2-chloroethylnitrosoureas has been determined. Guanines in the midst of a run of guanines are more susceptible than guanines in other base sequences. We have shown that certain 2-chloroethylnitrosoureas (BCNU, CCNU and methyl-CCNU) follow this same pattern. However, the quantitative degree of higher specificity for guanine with guanines as nearest neighbors depended on both the guanine position alkylated and the structure of the alkyl group attached. For example, when hydroxyethylation of runs of guanine occurred at N-7, a 6- to 11-fold increase of alkylation occurred compared to that found in the random base sequences of DNA, while hydroxyethylation at O-6 increased 1.2 to 3.5-fold and chloroethylation at N-7 was 2-to 4-fold higher than in DNA. Guanines with thymines on both the 3' and 5' sides were much less susceptible, most notably in N-7-hydroxyethylation and N-7-chloroethylation. Since guanine-rich regions are found in regulatory regions of the genome, knowledge concerning the effect of base sequence upon the production of each of the potential DNA lesions is vital to gaining an understanding of the roles of these lesions in the anti-tumor activity of a drug.

Alkylation↗
PubMed1993

Mutagenicity to Salmonella, Drosophila and the mouse bone marrow of the human antineoplastic agent fotemustine: prediction of carcinogenic potency.

The antineoplastic agent fotemustine is shown to be a base-pair mutagen to Salmonella. Activity is more marked in the uvrB-proficient strain G46 than in the repair-deficient strain TA1535. This is consistent with its ability to cross-link DNA. Potent activity as a somatic and germ-cell mutagen to Drosophila was also observed. A potent clastogenic response was given by fotemustine in the mouse bone marrow following either oral gavage or intraperitoneal injection of a single dose of 5 mg/kg. In each of these respects it is shown to be indistinguishable from the structurally related antineoplastic agent and human carcinogen MeCCNU. It is concluded that fotemustine should be regarded as having clear potential to induce cancer in humans. Based on these data, including the preponderance of chromosome breakages over recessive lethal mutations in Drosophila, an estimated rodent carcinogenic potency (TD50) of between 15-150 mg/kg is suggested for fotemustine.

Animals↗
PubMed1986

In vivo studies on the relationship between hepatic metabolism and the renal toxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU).

Administration of a single sc dose of the nephrotoxic anticancer agent 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) to rats led to a time-dependent decrease in renal function (i.e., renal slice anion accumulation, renal concentrating ability, and urinary output) which was correlated with the accumulation of carbamylating and alkylating intermediates of 14C-labeled MeCCNU that bound irreversibly to kidney protein. MeCCNU also produced a dose-dependent decrease in glutathione (GSH) preferentially in liver, but not in kidney. Pretreatment with piperonyl butoxide (PIP) decreased the renal toxicity and covalent binding of MeCCNU, and ameliorated the MeCCNU-dependent decrease in liver and kidney GSH. Radioactivity detected in the urine from the PIP-pretreated group was markedly lower than that in the MeCCNU-only group. In contrast, PIP pretreatment increased the accumulation of parent MeCCNU into fatty tissue. Pretreatment with phenobarbital (PB) increased the renal toxicity of MeCCNU. Moreover, PB pretreatment resulted in the increased alkylation of both liver and kidney macromolecules and to an increase in the urinary clearance of ethylene-labeled MeCCNU. In all experiments, modifiers of hepatic biotransformation produced changes in the level of covalent binding by ethylene-labeled MeCCNU (alkylation) which correlated with the degree of toxicity of MeCCNU in the kidney. Additional evidence supporting a role for hepatic biotransformation in the toxicity of MeCCNU was provided by an in vivo/in vitro colony-forming assay which demonstrated the presence of a cytotoxic metabolite in the bile of a MeCCNU-administered rat. These studies suggest that hepatic metabolism contributes significantly to the alkylating activity of MeCCNU in the liver and the kidney, and indicate that a liver-derived metabolite may be responsible for the renal toxicity of MeCCNU.

Animals↗
PubMed1986

Comparative nephrotoxicity of 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin: functional-structural correlations in the Fischer 344 rat.

1-(2-Chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (MeCCNU) and chlorozotocin (CZ; 2-[3-(2-chloroethyl)-3-nitrosoureido]-D-glucopyranose) are structurally related anticancer agents which differ by virtue of the increased water solubility, and comparatively low carbamylating activity, of CZ relative to MeCCNU. In the present study, a single sc injection of either of these chloroethylnitrosoureas was nephrotoxic to male Fischer 344 rats. However, at equimolar doses, CZ was shown to be a much more potent nephrotoxicant. A lethal 40-mg/kg dose of CZ (127 microM) initially resulted in acute tubular necrosis of the proximal tubules of the cortex, followed later by a necrosis of papillary collecting ducts. In contrast, lethal doses of MeCCNU (100-180 mg/kg; 400-730 microM) produced only minimal proximal tubule injury. A 250-mg/kg (1 mM) dose of MeCCNU resulted in massive papillary necrosis within 7 days, with only limited necrosis to the proximal tubules. Sublethal doses of either drug, resulted in a similar, chronic, progressive nephropathy which was delayed in onset and was characterized by polyuria, enzymuria, a decrease in urine concentrating ability, and in renal slice organic ion accumulation. Alterations in less sensitive indicators of renal toxicity (i.e., proteinuria, glucosuria, and elevated blood urea nitrogen) were observed no earlier than 3 to 7 days after administration of only the highest tested doses of CZ (40 mg/kg) or MeCCNU (250 mg/kg). At sublethal doses, administration of either drug resulted in karyomegaly to the collecting ducts in the renal medulla within 2 to 4 weeks. These studies demonstrate that carbamylation-mediated reactions may not be necessary for nephrotoxicity to develop following administration of this class of antitumor agent.

Animals↗
PubMed1983

Use of magnetic emulsion as a novel drug carrier for chemotherapeutic agents.

Magnetic guidance of magnetic emulsion for site specific delivery was investigated in vitro and in vivo. The magnetic emulsion was characterized in vitro for its magnetic responsiveness using a constant flow apparatus, and its high retention by magnetic field was confirmed. After intravenous injection in rat, magnetic emulsions were localized to the predetermined site (lungs) by application of an electromagnet to the lungs. Similarly, 1-(2-chloroethyl)-3-(trans-4-methylcyclohexyl)-1-nitrosourea (methyl-CCNU) contained in the dispersed oily phase of the emulsions, was also concentrated at the target-site. Such preferential localization by magnetic means suggested that magnetic emulsions could become effective drug carriers with site specificity for the delivery of chemotherapeutic agents in cancer chemotherapy.

Animals↗
PubMed1982

The oncostatic effect of methyl-CCNU on various experimental lymphoreticular neoplasms.

Studies on the chemotherapeutic potential of methyl-CCNU on experimental leukemias were undertaken. A number of murine transplantable in vivo lines (chemical carcinogen-induced T and B leukemias; radiation- and viral-induced T leukemias of C57BL/6, C3H/eb and SJL/J origin; radiation-induced myeloid leukemias and spontaneous reticulum cell neoplasms of SJL/J mine) were used in these studies. The optimal dose of methyl-CCNU and optimal timing of administration were extensively investigated on two sample lines of T cell leukemias of C57BL/6 mice. Leukemic cell eradication could be achieved in almost all of the different leukemias treated, irrespective of whether induction was brought about by chemical or physical means or due to a viral leukemogenic agent. Studies undertaken to elucidate the effect of methyl-CCNU on the establishment of preleukemic cells following induction of leukemia by the radiation leukemia virus (RadLV) or by total body irradiation, indicated the oncostatic effect of methyl-CCNU on early preleukemic cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1986

Biphenotypic leukemia with unusual chromosomal translocation in a patient treated for melanoma.

A patient in complete remission from malignant melanoma but with refractory anemia after nitrosourea treatment developed acute biphenotypic leukemia. This disease, progression was accompanied by expansion of a cytogenetically abnormal clone. At first cytogenetic analysis, 1 year post discontinuation of chemotherapy, only 25% of the metaphases examined were hypodiploid with monosomy 7. Six months later, all of the metaphases seen were 45,XY,-7. Six months before overt acute leukemia was diagnosed, an additional chromosome abnormality emerged, t(2;3)(q31;q27). Although the translocation was present in all metaphases examined, the patient progressed into an acute leukemia with two components: one TdT-positive, Ia-positive, and the other TdT-negative, Ia-positive, monocytoid antigen-positive. This mixed leukemia was identified by double fluorescence staining for intranuclear TdT and surface labeling with a monocyte-specific monoclonal antibody.

Acute Disease↗