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Pulmonary reactions to chemotherapeutic agents: the ‘chemotherapy lung’
Published in Philippe Camus, Edward C Rosenow, Drug-induced and Iatrogenic Respiratory Disease, 2010
Fabien Maldonado, Andrew H Limper
Chlorambucil is an alkylating agent used in the treatment of chronic lymphocytic leukaemia, Hodgkin’s disease and lowgrade non-Hodgkin’s lymphoma. It has occasionally been associated with the development of lung toxicity, usually within 6 months to a year of initiation of therapy. Most features of chlorambucil-induced lung toxicity are common to other alkylating agents, and usually occur after doses in excess of 2 g.1 The reported mortality is high. Discontinuation of the offending agent and corticosteroids may be of benefit.
Mechanisms of Different Anticancer Drugs
Published in Anjana Pandey, Saumya Srivastava, Recent Advances in Cancer Diagnostics and Therapy, 2022
Anjana Pandey, Saumya Srivastava
For ovarian cancer and lymphocytic leukemia treatment, chlorambucil has been used for the past 20 years (IARC working group, 2012). It is available commercially for oral use by absorption of the gastrointestinal tract. This drug is readily transported to cancerous cells through facilitated diffusion (Pocasap et al., 2020). It has the same action mechanism spectrum as other alkylating drugs for anticancer activity; rarely, it causes alopecia or toxicity of the bladder.
Composition of Proprietary Products Approved in the United States
Published in Sarfaraz K. Niazi, Handbook of Pharmaceutical Manufacturing Formulations, Third Edition, 2019
LEUKERAN (chlorambucil) is available in tablet form for oral administration. Each film-coated tablet contains 2 mg chlorambucil and the inactive ingredients colloidal silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline cellulose, red iron oxide, stearic acid, titanium dioxide, and yellow iron oxide.
Overview of biological mechanisms of human carcinogens
Published in Journal of Toxicology and Environmental Health, Part B, 2019
Nicholas Birkett, Mustafa Al-Zoughool, Michael Bird, Robert A. Baan, Jan Zielinski, Daniel Krewski
Chlorambucil forms covalent DNA adducts. The compound contains two chloro-ethyl groups, one of which reacts with the N7 position of guanine or adenine. The second chloro-ethyl group subsequently reacts with cellular proteins, or with a DNA base to form a stable DNA inter-strand cross-link, leading to mitotic delay. Failure to repair these lesions leads to mutations. Chlorambucil has been tested for genotoxicity in several short-term assays in vitro and in vivo. This compound is mutagenic in bacteria after metabolic activation. This drug produces a range of genetic damages including gene conversion in yeast, sex-linked recessive mutations in Drosophila, mutations in Chinese hamster ovary cells, and clastogenic effects in human lymphocytes in vitro, and in animals in vivo. Exposure to chlorambucil increases the frequency of micronuclei and chromosomal aberrations in rat bone-marrow and spleen in vivo.
Recent advances in multifunctional dendrimer-based nanoprobes for breast cancer theranostics
Published in Journal of Biomaterials Science, Polymer Edition, 2022
Prashant Kesharwani, Rahul Chadar, Rahul Shukla, Gaurav K. Jain, Geeta Aggarwal, Mohammed A.S. Abourehab, Amirhossein Sahebkar
Li et al had explored a novel approach where they studied the anticancer activity of dendrimers on BC cells. Poly lysine dendrimer were designed to co-ordinately bury selenium − platinum inside their core. Formed aggregates were stable, monodispersed, and of smaller size. Uptake of co-ordinated selenium − platinum was greater than individual selenium and platinum with dendrimer. Moreover, the antiproliferative activity of selenium − platinum co-ordinated-Poly lysine dendrimer against 4T1 BC cells was found to be similar to cisplatin. It was concluded that the coordinated delivery of selenium − platinum in dendrimer itself showed anticancer activity against BC cells by generating reactive oxygen species [87]. Similarly, Bielawski et al evaluated the cytotoxicity and antiproliferative activity of an amine-terminated dendrimer-chlorambucil against MDA-MB-231 and MCF-7 BC cells. Amine-terminated dendrimer-chlorambucil exhibited greater anticancer activity when compared to free chlorambucil. Chlorambucil was conjugated covalently with dendrimer by amide and ester bond leading to a specific pattern of drug release [88] The concentrations of chlorambucil needed to inhibit [3H] thymidine (within DNA) by 50% (IC50) was significantly higher than PAMAM–CH conjugate. The required amount of drug and PAMAM–CH conjugate for 50% decrease in [3H] thymidine encapsulation into DNA in MCF-7 cells (IC50) was found to be 64 ± 2 nM and 14 ± 2 nM, respectively after 24 hrs. Finally, data obtained from antiproliferative and thymidine incorporation inhibition studies revealed that dendrimer drug conjugate produced a great effect in comparison to the effects produced by free chlorambucil [89].
Understanding the influence of external perturbation on aziridinium ion formation
Published in Molecular Physics, 2018
Sourab Sinha, Pradip Kr Bhattacharyya
The R-group of nitrogen mustard drug (shown in Figure 1) differentiates the activity of the drug molecule during the alkylation mechanism. The R-group determines the chemical reactivity, active transport across bio-membranes, side effects, site of attack and oral bioavailability of the drug. For the present study, we have considered mustine (R = −CH3), the first and the simplest nitrogen mustard, chlorambucil (R = −C10H11O2) and melphalan (R = −C9H10NO2) from the nitrogen mustard family. Chlorambucil and melphalan have been registered as the most effective and reliable drugs in health practice in WHO's list of essential medicines [59]. The inductive properties of R-group play a significant role in the release of Cl− ion and formation of Az+ ion. Electron donating groups accelerates the activation of Az+ ion formation by donating electron density to the chloroethyl side chain, hence stabilising the product (Az+ ion) and enhancing the driving force of the reaction. The explicit water molecules, in the present study, act as a catalyst and the reaction, more specifically can be termed as ‘water assisted alkylation.’ DFT calculations in implicit solvation model are performed using water as solvent. Throughout the manuscript, the three drugs, mustine, chlorambucil and melphalan are abbreviated as mus, chlo and mel, respectively, and the adduct formation of drugs with water molecules are abbreviated as drug-H2O for adduct with one molecule of water, drug-2H2O for adduct with two molecules of water, drug-3H2O for adduct with three molecules of water and drug-4H2O for adduct with four molecules of water. In the following sections, we will discuss the variation in the structure and reactivity of the transition states of Az+ ion formation in the presence of explicit water molecules and whether it enhances the driving force of Az+ ion formation.