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At least 19 recordsLinked to original sources
PubMed1990

Pharmacokinetics of chlorambucil-tertiary butyl ester, a lipophilic chlorambucil derivative that achieves and maintains high concentrations in brain.

Equimolar doses of chlorambucil (10 mg/kg) and the lipophilic chlorambucil derivative, chlorambucil-tertiary butyl ester (13 mg/kg), were given i.v. to rats. Plasma and brain concentrations of chlorambucil and its active metabolites, 3,4-dehydrochlorambucil and phenylacetic mustard, as well as of chlorambucil-tertiary butyl ester were then determined by HPLC between 2 and 240 min after drug administration. Chlorambucil demonstrated a monophasic disappearance from plasma following its administration, with a half-life of 28 min. Significant amounts of phenylacetic mustard were detected after 15 min, and this agent maintained high levels of active compounds in plasma throughout the study. Only low concentrations of chlorambucil and phenylacetic mustard were detected in brain between 2 and 120 min. Following equimolar chlorambucil-tertiary butyl ester administration, it rapidly disappeared from plasma, with a half-life of approximately 2 min, and maintained low plateau concentrations between 15 and 120 min after treatment. It was not detected thereafter, although significant amounts of chlorambucil and phenylacetic mustard were detected throughout the study. Significant amounts of chlorambucil-tertiary butyl ester entered and remained within the brain, achieving a peak concentration at 15 min and disappearing thereafter with a half-life of 37 min. Low levels of chlorambucil and phenylacetic mustard were also detected. Calculated from the areas under the concentration vs time curves of total active compounds derived from chlorambucil and chlorambucil-tertiary butyl ester in brain and plasma, the brain:plasma concentration integral ratios were 0.018 and 0.68, respectively. Following equimolar doses of chlorambucil and chlorambucil-tertiary butyl ester, a 7-fold greater concentration integral was achieved by chlorambucil-tertiary butyl ester in brain at a 5-fold lower plasma concentration integral. Chlorambucil-tertiary butyl ester may be of value in the treatment of brain-sequestered tumors.

Alkylating Agents↗
PubMed1990

Cytotoxicity of chlorambucil and chlorambucil-fatty acid conjugates against human lymphomas and normal human peripheral blood lymphocytes.

The cytotoxic activity of chlorambucil (Chl) and of chlorambucil-fatty acid conjugates of different degree of unsaturation have been assayed in vitro upon two human lymphoma cell lines and comparatively, upon quiescent and mitogen-activated lymphocytes from healthy blood donors. The cell toxicity observed with Chl-arachidonic acid and Chl-docosahexaenoic acid against lymphoma cells was, at any experimental condition used, equal or higher than the individual toxic potential of either chlorambucil or fatty acids. The two conjugates, like chlorambucil alone, were toxic against mitogen-activated lymphocytes. Contrary to chlorambucil, Chl-arachidonic at any concentration tested, lacked of toxicity towards normal non-activated lymphocytes. Chl-oleic acid conjugate was, whatever the cell species tested, much less toxic than Chl alone. In conclusion, the coupling of chlorambucil with polyunsaturated fatty acids increases: (a) the selectivity against neoplastic versus quiescent lymphocytes and (b) the toxicity for B-lymphoma cells. The selective effect of Chl-fatty acid conjugates is discussed in relation with the expression of an AFP/AFP-receptor autocrine system in malignant lymphoblastoid cells and in mitogen-activated lymphocytes.

Arachidonic Acids↗
PubMed1990

Physicochemical and pharmacokinetic parameters of seven lipophilic chlorambucil esters designed for brain penetration.

This report describes the physicochemical and pharmacokinetic parameters of seven chlorambucil esters, which were compared with those of chlorambucil. These esters were designed as chlorambucil prodrugs to increase the brain penetration and concentration vs time profile of chlorambucil within the CNS for potential treatment of brain tumors. They include four aliphatic esters from one to eight carbon chains in length (chlorambucil-methyl, -propyl, -hexyl, and -octyl esters) and three aromatic esters, including the phenylmethyl, phenylethyl and prednisolone ester of chlorambucil, prednimustine. The esters were lipophilic and possessed log octanol:water partition coefficients (log P values) that ranged from 4.05 to greater than 8.0. All retained alkylating activity, which was reduced compared with that of chlorambucil. In addition, all were metabolized in vivo in the rat to yield chlorambucil alone. Measurement of the in vitro rate of ester hydrolysis of the compounds to yield chlorambucil in rat plasma demonstrated that short-chain aliphatic and aromatic chlorambucil esters were rapidly broken down to their parent compound. The plasma half-lives of the compounds increased with the increasing length and complexity of their ester chain. This may have been related to an increase in the binding of the long-chain esters to plasma proteins, protecting the ester from nonspecific plasma esterases, and to a reduced affinity of plasma esterases to these esters. Pharmacokinetic analysis of chlorambucil-hexyl, -octyl, and -prednisolone esters by HPLC demonstrated that following their intravenous administration in the rat (in doses equivalent to equimolar chlorambucil, 10 mg/kg), they yielded only low concentrations of active compounds in plasma and brain. The brain:plasma ratio of these was low and similar to that of chlorambucil, and no ester demonstrated anticancer activity superior to that obtained after the administration of equimolar chlorambucil (5 mg/kg i.v., days 1-5) against brain-sequestered Walker 256 carcinosarcoma in the rat.

Alkylating Agents↗
PubMed1992

Alterations in the activity and regulation of mammalian ribonucleotide reductase by chlorambucil, a DNA damaging agent.

Ribonucleotide reductase provides the four deoxyribonucleotides required for the synthesis of DNA. In this study, we examined the hypothesis that alterations in the regulation of ribonucleotide reductase activity may be necessary to provide the deoxyribonucleotides required for DNA repair, following exposure of mammalian cells to DNA damaging agents such as the antitumor agent chlorambucil. We observed a marked transient increase in ribonucleotide reductase activity within 2 h of exposing BALB/c 3T3 mouse cells to DNA damaging concentrations of chlorambucil. Northern blot analysis showed that elevations in activity were accompanied by transient increases in the mRNA levels of both genes (R1 and R2) that code for ribonucleotide reductase. Western blot analysis indicated that only the protein for the limiting component for enzyme activity, R2, was significantly elevated in chlorambucil treated cultures. The chlorambucil effects upon activity and regulation of ribonucleotide reductase occurred without any detectable changes in the rate of DNA synthesis, as would be expected if the elevation in enzyme activity is required for DNA repair. The chlorambucil-induced elevations in R1 and R2 message levels were blocked by treatment of cells with actinomycin D or the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, indicating the importance of the reductase transcriptional process in responding to the action of chlorambucil and providing evidence for the involvement of a protein kinase C pathway in the regulation of mammalian ribonucleotide reductase. In addition to the chlorambucil-induced elevations in enzyme activity, message, and protein levels, the drug was also shown to be an inhibitor of ribonucleotide reductase activity in cell-free preparations. Separation of ribonucleotide components on an affinity column followed by selective exposure of the protein components to chlorambucil showed that both R1 and R2 proteins were targets for chlorambucil, in keeping with the known alkylating abilities of the drug. These observations provide the first direct demonstration of a link between the regulation of mammalian ribonucleotide reductase and the process of DNA repair and contribute to our understanding of the mode of action of a class of drugs represented by chlorambucil, in which chemotherapeutic activity has been attributed to DNA damaging effects.

3T3 Cells↗
PubMed1992

Targeting of tumor cells and DNA by a chlorambucil-spermidine conjugate.

Many tumor cells, including murine ADJ/PC6 plasmacytoma cells, possess an active energy dependent polyamine uptake system which selectively accumulates endogenous polyamines and structurally related compounds. We have attempted to target the cytotoxic drug chlorambucil to a tumor possessing this uptake system by conjugating it to the polyamine spermidine. Furthermore, since polyamines have a high affinity for DNA, the attachment of spermidine to chlorambucil should also facilitate its targeting to DNA. This was supported by the observation that the chlorambucil-spermidine conjugate was approximately 10,000-fold more active than chlorambucil at forming interstrand crosslinks with naked DNA. In vitro cytotoxicity and in vivo antitumor studies were carried out using the ADJ/PC6 plasmacytoma. In vitro, using [3H]thymidine incorporation to assess cell viability following a 1-h exposure to control and polyamine depleted ADJ/PC6 cells, chlorambucil-spermidine was 35- and 225-fold, respectively, more toxic than chlorambucil. The increased toxicity of the conjugate compared to chlorambucil was possibly due to enhanced DNA binding and/or facilitated uptake via the polyamine uptake system. The enhanced toxicity of the conjugate but not chlorambucil by prior polyamine depletion with difluoromethylornithine, together with the observation that the conjugate but not chlorambucil competitively inhibited spermidine uptake into tumor cells, supported the suggestion that the conjugate utilized the polyamine uptake system. In vivo following a single i.p. dose, the conjugate was 4-fold more potent than chlorambucil in its ability to inhibit ADJ/PC6 tumor growth in BALB/c mice. However, the therapeutic index was not increased. Our results support the hypothesis that polyamines linked to cytotoxics facilitate their entry into tumor cells possessing a polyamine uptake system and increase their selectivity to DNA. This may have therapeutic application in the delivery of cytotoxic agents linked to polyamines to certain tumors.

Animals↗
PubMed1991

A pharmacokinetic study of prednimustine as compared with prednisolone plus chlorambucil in cancer patients.

The pharmacokinetic characteristics of prednisolone and of chlorambucil and its beta-oxidized metabolite, phenylacetic mustard (PAM) were studied in plasma after the oral administration of 200 mg prednimustine (Sterecyt) and a regimen consisting of 20 mg prednisolone plus 20 mg chlorambucil, respectively. A total of 12 cancer patients completed this trial. The drugs were given in a cross-over study as single doses, and serial plasma samples were collected for 32 h. Chlorambucil and PAM were assayed by a gas chromatographic/mass spectrometry method and prednisolone, by radioimmunoassay. The median relative availability of the prednisolone and chlorambucil moiety in prednimustine was 19% and 16%, respectively. Prednisolone, as well as chlorambucil and PAM, appeared later and at a significantly lower concentration in plasma after treatment with prednimustine as compared with the mixture of chlorambucil and prednisolone. We also found that the elimination phase of chlorambucil and PAM in plasma is prolonged after the administration of prednimustine as compared with chlorambucil per se. In contrast, the elimination of the prednisolone moiety of prednimustine and that following the administration of a plain prednisolone tablet did not seem to differ. The modified plasma profile of the alkylating components following prednimustine administration may be important for the clinical efficacy of prednimustine.

Adult↗
PubMed1991

Comparative pharmacokinetics of chlorambucil and prednimustine after oral administration.

The pharmacokinetics of chlorambucil, phenylacetic acid mustard (the beta-oxidation product of chlorambucil), and prednisolone were investigated in a cross-over study after oral administration of chlorambucil (30 mg) + prednisolone (50 mg) versus prednimustine (300 mg), the ester of chlorambucil and prednisolone. Intact prednimustine could not be detected in plasma at any time. After administration of prednimustine, the plasma concentration-time curves of chlorambucil, phenylacetic acid mustard, and prednisolone showed a retarded profile compared to the administration of the single components. The mean bioavailability was 14% for chlorambucil, 21% for phenylacetic acid mustard, and 22% for prednisolone, when given as prednimustine, compared to the administration of free compounds in stoichiometrically equivalent doses. When given in the oral dosages mentioned above, the average dose-intensity was 62% for chlorambucil, 95% for phenylacetic acid mustard, and 72% for prednisolone, indicating sufficient therapeutic concentrations of the detectable agents.

Administration, Oral↗
PubMed1990

Effects of chlorambucil and therapeutic decision in initial forms of chronic lymphocytic leukemia (stage A): results of a randomized clinical trial on 612 patients. The French Cooperative Group on Chronic Lymphocytic Leukemia.

In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which 612 good prognosis patients (stage A) received either no treatment (309 patients) or an indefinite course of chlorambucil at the daily dose of 0.1 mg/kg (303 patients). Overall survival appeared to be better in the untreated group (50 deceased patients compared with 62 in the chlorambucil group), but the difference was not significant (P = .21) even after adjusting for both prognostic and imbalanced factors (P = .09). The crude 5-year survival rates were 82% in the untreated group and 75% in the chlorambucil group. The action of chlorambucil appeared to be a complex phenomenon associating beneficial effects consisting in slowing down disease progression to stage B or C (P less than .01), and favoring disease remission with harmful effects given by a short survival after disease progression to stage B or C in the chlorambucil group and an increased incidence of epithelial cancers (33 v 19), as well as an excess of epithelial cancer deaths (13 v 3), in the chlorambucil group. As these results suggested an overall harmful effect of chlorambucil, we tried to define, within stage A patients, a group of patients with a low probability of disease progression. We showed that stage A patients with hemoglobin greater than or equal to 120 g/L and lymphocyte count less than 30 x 10(9)/L had a survival that was not significantly different (P = .46) from that of the age- and sex-matched French population. These patients, accounting for about 50% of all chronic lymphocytic leukemia patients, should not be treated unless disease progression is observed.

Adult↗
PubMed1979

The metabolism of deuterated analogues of chlorambucil by the rat.

The antitumour agent chlorambucil (4[4-bis(2-chloroethyl)aminophenyl]-butyric acid) is converted by beta-oxidation in vivo into phenylacetic mustard (2[4-bis(2-chloroethyl)aminophenyl]acetic acid). This process may be disadvantageous from a therapeutic viewpoint since the metabolite has half the therapeutic index of the parent drug against the Walker 256 carcinoma in rats. In seeking to retard beta-oxidation, selectively deuterated analogues have been synthesised and administered to rats. Plasma levels of phenylacetic mustard after giving chlorambucil-beta-d2 were lower than those given by unlabelled drug, but the therapeutic activity was not significantly altered by deuteration. A dehydro derivative of chlorambucil was detected as an intermediate in the beta-oxidation pathway. The isotopic compositions of this metabolite, and of recovered chlorambucil, were measured in plasma samples taken after giving labelled chlorambucil (alpha-d2 and beta-d2 variants) to rats. Deuterium was almost totally lost from the alpha-d2 form and from its metabolite after 30 min and partially lost in 10 min. The beta-d2 variant and its dehydro-derivative retained the label. Possible mechanisms for deuteration loss are discussed. The design of novel analogues, based on these metabolic studies, is proposed.

Animals↗
PubMed1976

Chlorambucil treatment of frequently relapsing nephrotic syndrome.

Chlorambucil, in combination with prednisone, was compared with prednisone alone in a randomized controlled trial in 21 children with either steroid-dependent or frequently relapsing nephrotic syndrome to assess its effect on the duration of remission and the rate of relapse. All control patients treated with prednisone alone continued to relapse at the same rate, with all patients experiencing a return of proteinuria by seven months. Conversely, those who received the same prednisone therapy along with chlorambucil for six to 12 weeks remained in complete remission, without further medication, during 12 to 34 months of follow-up observation. Complications were minimal. Immediate side effects commonly reported with cyclophosphamide were not seen with chlorambucil. Comparison with published reports also suggests that remission induced by chlorambucil is more stable than that after cyclophosphamide. Chlorambucil appears to be of value in the frequently relapsing nephrotic patient, adding an effect that is unattainable with prednisone alone.

Adolescent↗
PubMed1975

[Mode of action of chlorambucil. Initial metabolic studies using carbon 14 isotope labeling. Rheumatological implications of their results].

Mode of action of chlorambucil first metabolic studies by means of carbon-14 labelled isotpoes rheumatological implications of the results. Chlorambucil, gamma [rho-di(2-chloroethyl) aminophenyl] butyric acid, was labelled in either the carboxylic group (Ia), the mustard radical (Ib), or the carbon atom in the aplha position in the carboxylic group (Ic). The first studies by total autoradiography of mice, by organ fixation, by analysis of urine, faeces, and expired air of rats, and by microautoradiography of sections of organs and smears of tissues from rats and rabbits produced the following results: the metabolism of chlorambucil includes a long hepatic time; the molecule undergoes beta-oxidation almost certainly in the liver; thenthe oxidized form become localized in two potential target organs: the thymus and the bone marrow; there is no elective fixation in normal joints of any ot the three labelled compound studied; on the other hand, with all three molecules, there was elimination via the bile ducts, slight movement into the thoracic canal, and labeling ofHarder's glands (particularly with Ia and Ic); elimination of the three compounds in urine was complex. These facts suggest that chlorambucil undergoses activation in the liver, in the same way as cyclophosphamide; however, the similarity end there. The other steps in metabolism give rise to different molecules for these compounds. The high concentrations of chlorambucil in the thymus and the labelling of the marrow cells indicate that the action of this cytostatic compound is primarily immunodepressive.

Animals↗
PubMed1991

Chlorambucil treatment of sarcoidosis.

1) PURPOSE: To demonstrate usefulness of chlorambucil in patients with severe sarcoidosis unresponsive to, or intolerant of, corticosteroids. 2) PATIENTS AND METHODS: Corticosteroid therapy was required in 192 (48%) of 401 patients with sarcoidosis seen at Thomas Jefferson University Hospital 1985-89. Chlorambucil was given to 31 of these patients because complicating diseases or problems made adequate corticosteroid dosage impossible (5 cases) or because of failure of corticosteroid in tolerable doses to control the disease (26 cases). 3) RESULTS: Marked improvement was observed in 15 cases, and moderate improvement in 13 others. Chlorambucil was well tolerated and complications attributable to immunosuppression did not occur. A six month course of chlorambucil was often followed by relapse, and prolonged therapy in reduced dosage appears necessary in most patients requiring this treatment. 4) CONCLUSION: Failure of corticosteroids in tolerable dosage to control sarcoidosis is not uncommon, and in such patients chlorambucil treatment is a useful alternative.

Adult↗
PubMed1990

A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia.

In 1980, the French Cooperative Group on Chronic Lymphocytic Leukemia started a randomized clinical trial in which intermediate prognosis patients (stage B) received either an indefinite course of chlorambucil (0.1 mg/kg/d) or 12 cycles of the COP regimen (vincristine, cyclophosphamide, and prednisone). We present the results of the third interim analysis based on 291 patients (151 in the chlorambucil group and 140 in the COP group) with a mean follow-up of 53 months at the reference date of June 1, 1987. At this date, 129 deaths were observed, 65 in the chlorambucil group and 64 in the COP group; there was no improvement in overall survival with the COP regimen (P = .44) even after adjusting for both prognostic and imbalanced factors (P = .24). The 3-year and 5-year overall survival rates were, respectively, 69% and 44% in the chlorambucil group as compared with 73% and 43% in the COP group. The median survival times were 58 months in the chlorambucil group and 57 months in the COP group. Moreover, no significant difference was observed between the two treatment groups in terms of either treatment response, 9-month status, time to disease progression to stage C, or causes of death.

Chlorambucil↗
PubMed1990

Nitro analogues of chlorambucil as potential hypoxia-selective anti-tumour drugs.

The chlorambucil isomer 4-[3-[N,N-bis(2-chloroethyl)amino]phenyl] butanoic acid (m-chlorambucil) has been synthesized for the first time, and the two isometric nitro derivatives of both m-chlorambucil and chlorambucil itself have been prepared as potential hypoxia-selective cytotoxins. Reduction potentials (E1/2) of the two nitro compounds were determined by cyclic voltammetry, and one-electron reduction potentials (E(1] were estimated. Both the chlorambucil isomers and the derived nitro compounds crosslink DNA, as determined by their cytotoxicity ratios in DNA repair-proficient and -deficient cell lines, but neither of the nitro derivatives showed selective toxicity under hypoxic conditions, probably due to their rather low reduction potentials.

Animals↗
PubMed1975

In vitro cytotoxicity of anti-theta (Thy-1) antibodies combined with chlorambucil.

Two methods are described for linking chlorambucil to antibodies. At low pH an association is formed which is not stable under physiological conditions and the cytotoxicity is the result of the independent action of chlorambucil and antibody. At pH 8 a more stable linkage is formed and this complex shows specific toxicity for cells carrying the appropriate antigen. Uncombined chlorambucil and antibody are more cytotoxic that chlorambucil alone, especially if the cells are exposed first to the chlorambucil.

Animals↗
PubMed1990

Characterization of glutathione conjugates of chlorambucil by fast atom bombardment and thermospray liquid chromatography/mass spectrometry.

Chlorambucil (p-(di-2-chloroethyl)amino-gamma-phenylbutyric acid) is a bifunctional alkylating agent which exhibits acquired drug resistance upon repeated dosing in humans. This compound reacts with glutathione both non-enzymatically and enzymatically in the presence of immobilized microsomal glutathione-S-transferases to produce several glutathione conjugates. These conjugates result from displacement of one or both chlorines by the nucleophilic cysteine sulfhydryl moiety of glutathione. The mono- and diglutathionyl conjugates of chlorambucil were purified by reversed-phase high-performance liquid chromatography and characterized by positive ion fast atom bombardment mass spectrometry. In addition, the mono- and dihydroxy hydrolysis products of chlorambucil were characterized by positive ion thermospray liquid chromatography/mass spectrometry (LC/MS). The glutathione conjugates of chlorambucil did not produce molecular ion species in thermospray LC/MS mode, but gave characteristic ions at m/z 147 corresponding to fragmentation of the glutathione moiety. The formation of glutathione conjugates of this class of alkylating agents may play a role in the development of acquired drug resistance.

Animals↗
PubMed1992

Comparison of cyclosporin and chlorambucil in the treatment of steroid-dependent idiopathic nephrotic syndrome: a multicentre randomized controlled trial. The French Society of Paediatric Nephrology.

Forty children with steroid-dependent idiopathic nephrotic syndrome and signs of steroid toxicity were randomly assigned to receive either cyclosporin 6 mg/kg body wt. per day for 3 months and at tapering doses over the next 3 months or chlorambucil at a cumulative dose of 8 mg/kg body wt. The two groups of patients did not differ significantly in sex distribution, age of onset of disease, duration of disease, number of relapses and histological findings. Of the 20 patients treated with cyclosporin, 4 relapsed before or on discontinuation of prednisone, 7 relapsed when the initial dose of cyclosporin was tapered, and 8 after withdrawal of cyclosporin. Of the 20 patients treated with chlorambucil, 14 relapsed while 6 were still in remission 27-49 months after completion of the treatment course. Thus the actuarial remission rate at 2 years was 45% after a course of chlorambucil compared with only 5% after a 3-month course of cyclosporin. We believe that children with steroid-dependent idiopathic nephrotic syndrome should be treated with a course of chlorambucil before resorting to cyclosporin.

Adolescent↗