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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↗
PubMed2001

Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

Administration, Oral↗
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↗
PubMed1994

The comparative toxicity of chlorambucil and chlorambucil-spermidine conjugate to BALB/c mice.

The acute intraperitoneal toxicities of chlorambucil and chlorambucil-spermidine conjugate have been compared, in mice. Both compounds were neurotoxic and also caused a prolonged fall in bodyweight and a depletion of lymphocyte numbers associated with a fall in the total leukocyte count and loss of spleen and thymus weight. Alanine aminotransferase and aspartate aminotransferase activities and blood urea nitrogen concentration were increased at 24 h after conjugate administration, but had returned to normal at 72 h. Chlorambucil significantly decreased blood urea nitrogen concentration for 72 h, but did not affect transferase activity. Tissue concentrations of conjugate were measurable in liver and kidney for 12 days and lung for 5 days after dosing. The toxicity of both compounds was cumulative. In mol/kg, the chlorambucil-spermidine conjugate was 10-fold more toxic than chlorambucil, on the basis of their neurotoxicity, but only 2- to 3-fold more toxic on the basis of their effects on lymphocyte depression. The increased toxicity of the conjugate does not improve its therapeutic index relative to chlorambucil.

Alanine Transaminase↗
PubMed1980

Chlorambucil inhibition by dimethyl sulfoxide and thiosulfate: implications for chlorambucil chemotherapy.

Chlorambucil alkylation of pyridine, a model for nucleotides, appears to be first order in chlorambucil, but zero order in pyridine, and is strongly inhibited by dimethylsulfoxide. The same results are seen with chlorambucilyl [3H]prolyl proline; full alkylation activity was regained upon removal of dimethylsulfoxide. Chlorambycilyl [3H]prolyl proline alkylation of tRNA also appears to be first order in alkylator, but somewhat dependent on tRNA concentration, and is also strongly inhibited by dimethylsulfoxide. 10 mM Na2S2O3 completely inhibits alkylation by aqueous 1 mM chlorambucil. Up to 1 M chlorambucil in Me2SO retains full alkylation activity for at least a year. We suggest that the risk of carcinogenesis inherent in chlorambucil chemotherapy may be avoided by the topical application or injection of 1 M chlorambucil in Me2SO, in conjunction with oral administration of Na2S2O3.

Alkylation↗
PubMed1985

Comparative carcinogenic activity of prednimustine, chlorambucil, prednisolone and chlorambucil plus prednisolone in Sprague-Dawley rats.

This study compares long term toxic effects of equivalent doses of prednimustine (12 mg/kg) chlorambucil (3 mg/kg), prednisolone (3 mg/kg) and chlorambucil plus prednisolone (3 mg/kg each) in comparison to vehicle treated controls after regular administration over a period of 18 months to 600 female Sprague Dawley rats. Frequency of administration to subgroups (30 rats each) varied between 9 (a), 4.5 (b), 2 (c) times or once (d) a month. When comparing organ specific, age-adjusted expected versus observed incidences after natural death of animals an increased tumor risk was found in organ systems of all treatment modalities but prednisolone. Prednimustine-administration was related to an elevated risk of developing squamous-cell carcinomas of the external auditory canal only (alpha = 0.013), whereas simultaneous application of chlorambucil plus prednisolone induced significantly higher rates of adenocarcinomas of the mammary gland, of malignant tumors of the central and peripheral nervous tissue and of squamous cell carcinomas of the external auditory canal (alpha less than 0.01 for each tissue). Chlorambucil alone caused a significantly higher rate of malignancies of the hematopoietic and lymphatic tissue (alpha less than 0.01) additionally to effects observed after the unlinked mixture of chlorambucil plus prednisolone. There is evidence of carcinogenic activity of prednimustine compared to untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or of chlorambucilalone.

Animals↗
PubMed1986

Long-term toxicology effects of prednimustine in comparison with chlorambucil, prednisolone, and chlorambucil plus prednisolone in Sprague-Dawley rats.

Chlorambucil was linked to prednisolone to improve the therapeutic and toxic properties of this potent alkylating agent, which is known to induce second tumors in humans. To compare the carcinogenic potency of the linked compound with that of the respective individual agents and of their unlinked mixture, prednimustine (I), chlorambucil (II), prednisolone (III), chlorambucil plus prednisolone (IV), or vehicle were administered to groups of 120 female Sprague-Dawley rats for 18 months. The following doses were administered nine, four, five, two times, or once a month per subgroup of 30 rats: I, 12 mg/kg; II, 3 mg/kg; III, 3 mg/kg; IV, 3 mg/kg. After natural death of animals, median survival times were analyzed, and percentages of malignant tumors were recorded. An increased tumor risk was found in the following organs compared with those of vehicle-treated controls: I, external auditory canal (EAC); II, mammary gland (MG), central and peripheral nervous tissue (CPNT), hematopoietic and lymphatic tissue (HLT), and EAC; III, none; and IV, MG, CPNT, and EAC. There is evidence of carcinogenic activity of prednimustine compared with untreated controls, but the cancer-inducing potential of the linked compound is distinctly lower than that of the unlinked mixture of chlorambucil plus prednisolone or that of chlorambucil.

Animals↗
PubMed1985

Chlorambucil central nervous toxicity: a significant side effect of chlorambucil therapy in childhood nephrotic syndrome.

Chlorambucil (CHL) was used in combination with prednisolone in the treatment of nine children with frequently relapsing nephrotic syndrome. Serial electroencephalograms were obtained to evaluate CHL central nervous toxicity, before, during and after treatment with this agent. EEG abnormalities were observed in two of the nine children during chlorambucil therapy. EEG changes were diffuse spike and wave complexes and disappeared after discontinuation of therapy. There were no other neurological abnormalities and more particularly, no seizures or myocloni were observed. According to the literature, chlorambucil central nervous toxicity is found almost exclusively in childhood nephrotic syndrome. Strict neurological supervision of patients treated with chlorambucil is recommended.

Brain↗
PubMed1983

Studies with chlorambucil. I. Effect on lactate dehydrogenase in the testes of albino rabbits treated with multiple doses of chlorambucil.

Treatment with multiple sub-lethal doses of chlorambucil resulted in lower activity levels and specific activity of LDH and low protein content in the testes of albino rabbits. Electrophoretic analysis and assay of individual isozymes eluted from DEAE-Sephadex A-50 indicated that this loss in activity was related to the differential and/or selective action of chlorambucil on LDH4, which was affected most, while LDH3 and LDH5 were affected to a lesser degree. Kinetic inhibitory studies on purified rabbit muscle LDH in vitro revealed that chlorambucil in the reaction mixture binds to non-active enzyme sites resulting in non-competitive irreversible inhibition of LDH.

Animals↗
PubMed1981

Randomised trial comparing low-dose cisplatin and chlorambucil with low-dose cisplatin, chlorambucil, and doxorubicin in advanced ovarian carcinoma.

Ninety-eight patients with advanced ovarian cancer took part in a prospective, randomised trial comparing low-dose cisplatin and chlorambucil with low-dose cisplatin, chlorambucil, and doxorubicin. After 4 years response rates (greater than 50%) and proportion of complete remissions (28%) were similar in both groups. Median duration of remission was longest in the complete remitters, being 31 months in those having cisplatin and chlorambucil, and 24 months in those having doxorubicin as well.

Adenocarcinoma↗
PubMed1988

High dose continuous chlorambucil vs intermittent chlorambucil plus prednisone for treatment of B-CLL--IGCI CLL-01 trial.

279 B-CLL patients entered randomized IGCI clinical trial to compare the remission rate and survival of high dose continuous chlorambucil (regimen A) vs intermittent chlorambucil plus prednisone (regimen B), and to assess the effect of early treatment on survival. Regimen A was significantly better for remission induction (p less than 0.001), and prolonged survival (p less than 0.01) in comparison to regimen B. More aggressive chemotherapy is associated with better response but requires close monitoring of both antineoplastic effect and haematological toxicity. Total tumor mass score (TTM) proved to be suitable for definition of both early, stable disease and the response to therapy because of its quantitative continuous character and its independence of bone marrow failure. This system is helpful for the detection of treatment toxicity and consequently enables safe monitoring of therapy. Although statistically significant difference has not yet been reached between the patients treated early and non treated patients the latter group seems to fare better.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil.

The lipophilic derivatives of the anticancer alkylating agent chlorambucil, chlorambucil-methyl, -isopropyl and -tertiary butyl esters, were synthesized and administered i.v. to anesthetized rats. Plasma and brain concentrations of these agents and of their active metabolites, chlorambucil and phenylacetic mustard, then were determined by high-performance liquid chromatography between 5 and 60 min. Whereas large amounts of chlorambucil-tertiary butyl ester entered and were maintained in brain, lower amounts of chlorambucil-isopropyl ester and no chlorambucil-methyl ester were found in brain. The comparative brain/plasma concentration-time integral ratios of the total active agents generated from chlorambucil-tertiary butyl, -isopropyl and -methyl esters were 0.85, 0.12 and 0.06, respectively, compared to a ratio of 0.02 for chlorambucil. In vitro alkylating activity of each ester was compared to that of equimolar chlorambucil, by reaction with 4-(p-nitrobenzyl)pyridine. Each ester possessed high intrinsic alkylating activity, equal to 38.4, 57.0 and 69.9% of chlorambucil activity, for the -tertiary butyl, -isopropyl and -methyl esters, respectively. Therefore each is an active antineoplastic agent irrespective of whether or not chlorambucil is regenerated. The rates of ester hydrolysis of these derivatives to chlorambucil were measured in fresh rat blood and in liver and brain homogenates at 37 degrees C. Chlorambucil-methyl and -isopropyl esters were hydrolysed quickly within 30 s in blood and liver, whereas chlorambucil-tertiary butyl ester was more stable with half-lives of approximately 7 h and 2 h, respectively. All proved to be relatively stable in brain homogenate. Steric hindrance around the ester linkage of chlorambucil-tertiary butyl ester reduces its affinity to and rate of hydrolysis by plasma and liver esterases, and allows it to accumulate within the brain. Chlorambucil-tertiary butyl ester maintains high levels in brain despite rapidly declining plasma concentrations and, due to these favorable pharmacokinetics and to its intrinsic anticancer activity, it possess promising characteristics for the treatment of malignant brain tumors.

Alkylating Agents↗
PubMed1997

Myoclonus due to chlorambucil in two adults with lymphoma.

OBJECTIVE: To report myoclonus due to chlorambucil therapy in two adults with lymphoma, and to review the literature of chlorambucil neurotoxicity in adults. CASE SUMMARIES: Case 1: An 81-year-old man with lymphoma being treated with chlorambucil developed jerking movements and stiffness that persisted for 3 days and intensified at night. The dosage of chlorambucil was decreased with a subsequent decrease in symptomatology. Resolution of the myoclonus occurred with discontinuation of the chlorambucil. Rechallenge evoked a return of tremors the next day that later became constant and again resolved on discontinuation of chlorambucil. Case 2: A 75-year-old woman with lymphoma being treated with chlorambucil developed jerking movements in her limbs, particularly in her arms and right hip. The symptoms were so severe they prevented the patient from leaving her house. All symptoms resolved within 2-3 days after the cycle was completed and did not return. She was diagnosed as having had chlorambucil-induced myoclonus. DATA SOURCES: Searches were performed on MEDLINE, CancerLit, and Science Citation Index Review to identify reports and articles discussing chlorambucil-induced neurotoxicity, particularly myoclonus. DISCUSSION: Chlorambucil-induced myoclonus has been described in overdose situations and in the treatment of nephrotic syndrome in children. Three cases of reversible myoclonic activity associated with high-dose chlorambucil in adults have also been described. In each case, the myoclonus resolved following discontinuation of the drug. Only one other conclusive case of low-dose chlorambucil-induced myoclonus in an adult has been described. The two cases presented here are unique in that the myoclonus occurred in adults receiving low-dose chlorambucil who had no myoclonus before or after treatment with the drug. CONCLUSIONS: From the cases reviewed, it appears that chlorambucil may induce myoclonus in adults receiving therapeutic dosages of chlorambucil. The neurologic status of patients receiving chlorambucil should be followed closely during treatment. If myoclonus develops, drug-induced myoclonus should be considered, as well as discontinuation of the drug.

Aged↗
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↗
PubMed2000

Pharmacokinetics of chlorambucil in patients with chronic lymphocytic leukaemia: comparison of different days, cycles and doses.

The effects of repeated treatment cycles and different doses on intraindividual variation in oral bioavailability of chlorambucil and its first, active, and more toxic metabolite, phenylacetic acid mustard, were studied. Chlorambucil and phenylacetic acid mustard concentrations were measured with HPLC on Day 1 and on Day 4 in 15 timed blood samples from 11 chronic lymphocytic leukaemia patients receiving chlorambucil therapy cycles. Bioavailability was evaluated also after the first chlorambucil doses of six consecutive treatment cycles repeated every 4 weeks with increasing chlorambucil doses starting with 0.8 mg/kg/4 days, and increased by 0.1 mg/kg/4 days cycle. Area under the concentration-time-curve (AUC) from t=0 to infinite was in average 3.2 hr* microg/ml for the first cycle, and decreased by 17% in four days (P<0.05). The mean distribution half-life of chlorambucil was 0.49 hr and the terminal elimination half-life 2.45 hr. The bioavailability of chlorambucil decreased further when 4-day treatment cycles were repeated. For the fifth cycle, dose-corrected AUC for the first 2 hr was 33% smaller than that for the first cycle (P for trend <0.01). Data suggest accelerated metabolism and elimination of chlorambucil and phenylacetic acid mustard, but reduced oral bioavailability of chlorambucil cannot be excluded. However, except for AUC, none of the pharmacokinetic parameters of chlorambucil changed significantly during the first 4-day treatment period. The maximal plasma concentration and AUC of phenylacetic acid mustard did not change significantly during repeated treatment cycles. According to this trial a dose adjustment of chlorambucil is not necessary during a short-term course, but may be necessary when treatment cycles are repeated. An average increase in the chlorambucil dose of 10% per cycle maintains similar plasma concentration of chlorambucil.

Administration, Oral↗
PubMed1998

Albumin conjugates of the anticancer drug chlorambucil: synthesis, characterization, and in vitro efficacy.

In our efforts to improve the selectivity and toxicity profile of antitumor agents, four maleimide derivatives of chlorambucil (1-4) were bound to thiolated human serum albumin which differ in the stability of the chemical link between drug and spacer. 1 is an aliphatic maleimide ester derivative of chlorambucil, whereas 2-4 are acetaldehyde, acetophenone, and benzaldehyde carboxylic hydrazone derivatives. HPLC stability studies at pH 5.0 with the related model compounds 5, 7, 8, and 9, in which chlorambucil was substituted by 4-phenylbutyric acid, demonstrated that the carboxylic hydrazone derivatives have acid-sensitive properties; the acid lability of 7 was particular prominent with a half-life of only a few hours. The alkylating activity of albumin-bound chlorambucil was determined with the aid of 4-(4-nitrobenzyl)-pyridine (NBP), demonstrating that on average three equivalents were protein-bound. Evaluation of the cytotoxicity of free chlorambucil and the respective albumin conjugates in the MCF7 mamma carcinoma and MOLT4 leukemia cell line employing a propidium iodide fluorescence assay demonstrated that the conjugate in which chlorambucil was bound to albumin through an ester bond was not as active as chlorambucil. In contrast, the conjugates in which chlorambucil was bound to albumin through carboxylic hydrazone bonds were as or more active than chlorambucil in both cell lines. In particular, the conjugate in which chlorambucil was bound to albumin through an acetaldehyde carboxylic hydrazone bond exhibited IC50 values which were approximately 4-fold (MCF7) to 13-fold (MOLT4) lower than those of chlorambucil. Preliminary toxicity studies in mice showed that this conjugate can be administered at higher doses in comparison to unbound chlorambucil.

Animals↗