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Journal of Clinical Oncology : Official... Sep 2014Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as... (Review)
Review
PURPOSE
Chemoimmunotherapy has been the standard of care for chronic lymphocytic leukemia (CLL). However, the introduction of B-cell receptor (BCR) kinase inhibitors such as ibrutinib has the potential to eliminate the role of chemotherapy in the treatment of CLL. How to best incorporate old and new therapies for CLL in this landscape is increasingly complex.
METHODS
This article reviews current data available to clinicians and integrates these data to provide a strategy that can be used to approach the treatment of CLL in the era of BCR signaling inhibitors.
RESULTS
Current strategies separate patients based on age or functional status as well as genetics [presence or absence of del(17)(p13.1)]. In the era of targeted therapy, this will likely continue based on current available data. Phase III studies support chemoimmunotherapy as the initial standard therapy for patients without del(17)(p13.1). Choice of chemotherapy (fludarabine plus cyclophosphamide, bendamustine, or chlorambucil) and anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) varies based on regimen and patient status. For patients with del(17)(p13.1), no standard initial therapy exists, although several options supported by phase II clinical trials (methylprednisolone plus alemtuzumab or ibrutinib) seem better than chemoimmunotherapy. Treatment of relapsed CLL seems to be best supported by ibrutinib-based therapy. Completion of trials with ibrutinib and other new agents in the near future will offer opportunity for chemotherapy-free treatment across all groups of CLL.
CONCLUSION
Therapy for CLL has evolved significantly over the past decade with introduction of targeted therapy for CLL. This has the potential to completely transform how CLL is treated in the future.
Topics: Adenine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Chlorambucil; Cyclophosphamide; Drug Resistance, Neoplasm; Gene Deletion; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Molecular Targeted Therapy; Nitrogen Mustard Compounds; Piperidines; Practice Patterns, Physicians'; Purines; Pyrazoles; Pyrimidines; Quinazolinones; Vidarabine
PubMed: 25049322
DOI: 10.1200/JCO.2014.55.8262 -
Future Medicinal Chemistry Jun 2017
Topics: Antineoplastic Agents; Autophagy; Humans; Medicine, Chinese Traditional; Neoplasms; Nitrogen Mustard Compounds
PubMed: 28635310
DOI: 10.4155/fmc-2017-0081 -
British Journal of Pharmacology Jul 2010We investigated how McN-A-343 inhibited the alkylation of the M(1) muscarinic receptor by its nitrogen mustard derivative and that of ACh to identify whether it...
BACKGROUND AND PURPOSE
We investigated how McN-A-343 inhibited the alkylation of the M(1) muscarinic receptor by its nitrogen mustard derivative and that of ACh to identify whether it interacts allosterically or orthosterically.
EXPERIMENTAL APPROACH
We incubated the M(1) muscarinic receptor expressed in Chinese hamster ovary cells with ACh mustard for various periods of time in the presence of McN-A-343 or known allosteric and orthosteric ligands. After stopping the reaction and removing unreacted ligands, unalkylated receptors were measured using [(3)H]N-methylscopolamine. Analogous experiments were done using a nitrogen mustard analog of McN-A-343. Affinity constants, cooperativity values for allosteric interactions and rate constants for receptor alkylation were estimated using a mathematical model.
KEY RESULTS
The kinetics of receptor alkylation by the nitrogen mustard derivatives of ACh and McN-A-343 were consistent with a two-step model in which the aziridinium ion rapidly forms a reversible receptor complex, which converts to a covalent complex at a slower rate. The inhibition of receptor alkylation by acetycholine, N-methylscopolamine and McN-A-343 was consistent with competitive inhibition, whereas that caused by gallamine was consistent with allosterism. Affinity constants estimated from alkylation kinetics agreed with those measured by displacement of [(3)H]N-methylscopolamine binding.
CONCLUSIONS AND IMPLICATIONS
Our results suggest that McN-A-343 and its nitrogen mustard derivative interact competitively with ACh and N-methylscopolamine at the orthosteric site on the M(1) muscarinic receptor. Measuring how drugs modulate the kinetics of receptor alkylation by an irreversible ligand is a powerful approach for distinguishing between negative allosteric modulators and competitive inhibitors.
Topics: (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; Acetylcholine; Alkylation; Animals; CHO Cells; Cricetinae; Cricetulus; Male; N-Methylscopolamine; Nitrogen Mustard Compounds; Rats; Rats, Sprague-Dawley; Receptor, Muscarinic M1
PubMed: 20590642
DOI: 10.1111/j.1476-5381.2010.00810.x -
Molecules (Basel, Switzerland) Jun 2021A series of new analogs of nitrogen mustards (-) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition...
A series of new analogs of nitrogen mustards (-) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and -secretase (BACE1) enzymes. The AChE inhibitory activity studies were carried out using Ellman's colorimetric method, and the BACE1 inhibitory activity studies were carried out using fluorescence resonance energy transfer (FRET). All compounds displayed considerable AChE and BACE1 inhibition. The most active against both AChE and BACE1 enzymes were compounds and , with an inhibitory concentration of AChE IC = 0.051 µM; 0.055 µM and BACE1 IC = 9.00 µM; 11.09 µM, respectively.
Topics: Acetylcholinesterase; Amyloid Precursor Protein Secretases; Aspartic Acid Endopeptidases; Cholinesterase Inhibitors; GPI-Linked Proteins; Humans; Nitrogen Mustard Compounds; Peptides; Triazines
PubMed: 34203347
DOI: 10.3390/molecules26133942 -
The American Journal of Pathology Oct 1985When applied topically to the skin of rabbits in vivo, sulfur mustard (SM), the vesicant used in World War I, produced a slowly developing inflammatory response, which...
Inflammatory mediators and modulators released in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. I. Quantitative histopathology; PMN, basophil, and mononuclear cell survival; and unbound (serum) protein content.
When applied topically to the skin of rabbits in vivo, sulfur mustard (SM), the vesicant used in World War I, produced a slowly developing inflammatory response, which peaked in size at 1 and 2 days, ulcerated within 3 days, and reepithelialized by 10 days. Histologically, basophils and polymorphonuclear leukocytes (PMNs) were common in both early and late lesions, and the crust over the ulcers was composed of dead epidermal cells, fibrin, and large numbers of PMNs. Healing occurred under the crust by migration of epidermal cells from the margins of the lesions and from the hair follicles. In organ culture, the lesion explants survived well, and reepithelialization even took place. Their excellent survival enabled us to compare the life spans of the infiltrating leukocytes within an inflammatory site. PMNs within the explants began disappearing during the first day of culture, and almost all had disappeared by 3 days. In contrast, over half of the basophils and the mononuclear cells within the explants were still present after 3 days of culture. The 1-, 2-, 3-, 6-, and 10-day (1.0-sq cm) SM lesion biopsies showed a 30-45% increase in weight (when compared with normal skin), presumably due to the extravasation of serum proteins and the fluids retained by them. When the biopsies were organ-cultured for 3 days, the 1-, 2-, and 3-day lesions lost weight, and the 6- and 10-day lesions (and normal skin) gained weight. These weight differences were not due to the amount of unbound protein extractable into the culture fluids, because both the early lesions and the late lesions contained about the same amount of unbound protein. The most likely explanation for these weight differences is that the newly formed ground substances of late lesions absorbed culture fluid, because the ground substance had changed from the sol state of acute inflammation (in which it was extractable) back to its normal gel state (in which it was not extractable). The unbound protein extractable into the culture fluids was mostly of serum origin. This protein averaged 1.9 mg for 1.0 sq cm normal skin explants (with a mean weight of 215 mg), and 6.4 mg for 1-day SM lesions (with a mean weight of 313 mg). Because rabbit serum contains about 60 mg protein/ml, these figures indicate that normal skin contained about 15% (unbound) serum by weight.(ABSTRACT TRUNCATED AT 400 WORDS)
Topics: Animals; Basophils; Blood Proteins; Cell Count; Cell Survival; Inflammation; Lymphocytes; Macrophages; Mast Cells; Monocytes; Mustard Compounds; Mustard Gas; Neutrophils; Organ Culture Techniques; Protein Binding; Rabbits; Skin
PubMed: 4050973
DOI: No ID Found -
BMC Cancer Jul 2020Despite an improvement of prognosis in breast and colon cancer, the outcome of the metastatic disease is still severe. Microevolution of cancer cells often leads to drug...
BACKGROUND
Despite an improvement of prognosis in breast and colon cancer, the outcome of the metastatic disease is still severe. Microevolution of cancer cells often leads to drug resistance and tumor-recurrence. To target the driving forces of the tumor microevolution, we focused on synergistic drug combinations of selected compounds. The aim is to prevent the tumor from evolving in order to stabilize disease remission. To identify synergisms in a high number of compounds, we propose here a three-step concept that is cost efficient, independent of high-throughput machines and reliable in its predictions.
METHODS
We created dose response curves using MTT- and SRB-assays with 14 different compounds in MCF-7, HT-29 and MDA-MB-231 cells. In order to efficiently screen for synergies, we developed a screening tool in which 14 drugs were combined (91 combinations) in MCF-7 and HT-29 using EC or less. The most promising combinations were verified by the method of Chou and Talalay.
RESULTS
All 14 compounds exhibit antitumor effects on each of the three cell lines. The screening tool resulted in 19 potential synergisms detected in HT-29 (20.9%) and 27 in MCF-7 (29.7%). Seven of the top combinations were further verified over the whole dose response curve, and for five combinations a significant synergy could be confirmed. The combination Nutlin-3 (inhibition of MDM2) and PX-478 (inhibition of HIF-1α) could be confirmed for all three cell lines. The same accounts for the combination of Dichloroacetate (PDH activation) and NHI-2 (LDH-A inhibition). Our screening method proved to be an efficient tool that is reliable in its projections.
CONCLUSIONS
The presented three-step concept proved to be cost- and time-efficient with respect to the resulting data. The newly found combinations show promising results in MCF-7, HT-29 and MDA-MB231 cancer cells.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Line, Tumor; Colonic Neoplasms; Dichloroacetic Acid; Drug Screening Assays, Antitumor; Drug Synergism; Female; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Imidazoles; L-Lactate Dehydrogenase; Mustard Compounds; Phenylpropionates; Piperazines; Proto-Oncogene Proteins c-mdm2; Pyruvate Dehydrogenase Complex; Reproducibility of Results
PubMed: 32615946
DOI: 10.1186/s12885-020-07062-2 -
Canadian Medical Association Journal Jan 1971
Review
Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Bone Marrow; Bone Marrow Cells; Cell Division; Cyclophosphamide; Cytarabine; Female; Fluorouracil; Humans; Leukemia L1210; Leukemia, Lymphoid; Lymphoma; Melphalan; Mercaptopurine; Methotrexate; Mice; Multiple Myeloma; Neoplasms; Nitrogen Mustard Compounds; Prednisone; Pregnancy; Time Factors; Trophoblastic Neoplasms; Vinblastine
PubMed: 4322068
DOI: No ID Found -
British Journal of Haematology Jan 2013The management of patients with Hodgkin lymphoma (HL) recurring after stem cell transplantation (SCT) and multiply relapsed disease remains challenging. We report on 41...
The management of patients with Hodgkin lymphoma (HL) recurring after stem cell transplantation (SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90-120 mg/m(2) every 21 or 28 d. At first assessment (2-4 cycles), the overall response rate (ORR) was 78% with 12 (29%) complete (CR) and 20 (49%) partial responses (PR). Upon treatment prolongation to 6-8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Bendamustine Hydrochloride; Cell Cycle Checkpoints; Combined Modality Therapy; DNA Repair; Disease-Free Survival; Drug Evaluation; Female; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Male; Middle Aged; Nitrogen Mustard Compounds; Off-Label Use; Recurrence; Retrospective Studies; Salvage Therapy; Transplantation, Homologous; Treatment Outcome; Young Adult
PubMed: 23167437
DOI: 10.1111/bjh.12120 -
British Journal of Clinical Pharmacology Oct 1980Simple, accurate and specific gas-chromatographic methods for the estimation of derivatized phosphoramide and non-nitrogen mustards utilizing alkali-flame ionization...
Simple, accurate and specific gas-chromatographic methods for the estimation of derivatized phosphoramide and non-nitrogen mustards utilizing alkali-flame ionization detection are described. The pharmacokinetics in plasma of cyclophosphamide, phosphoramide mustard, nor-nitrogen mustard and nitrobenzyl pyridine alkylating activity were investigated following administration of cyclophosphamide by intravenous and oral routes to patients with malignant disease The mean for cyclophosphamide was 8.88 h (s.d. 1.25 h) and the apparent volume of distribution (Vβ) was 0.74 l kg (s.d. 0.16 l kg). The decline in plasma concentration of phosphoramide mustard was biphasic, the longer being 8.68 h (s.d. 2.50 h). This was not significantly different from that of cyclophosphamide. This could indicate that the true biological for phosphoramide mustard is identical with or shorter than that of cyclophosphamide. The plasma concentrations of phosphoramide mustard following cyclophosphamide doses of known therapeutic efficacy are probably insufficient to produce important cytotoxic effects. This suggests that if phosphoramide mustard is the major alkylating metabolite derived from cyclophosphamide, it is transported in the blood in precursor form. The mean plasma of nor-nitrogen mustard was 3.31 h (s.d. 1.60 h) which was significantly different from that of cyclophosphamide. The mean plasma of the nitrobenzylpyridine alkylating activity was 9.81 h (s.d. 4.18 h) and did not significantly differ from that of cyclophosphamide. Although the area under the plasma alkylating activity concentration, time curve is related to the of cyclophosphamide, the alkylating activity does not reflect the concentrations of the two plasma metabolites measured.
Topics: Aged; Alkylation; Chromatography, Gas; Cyclophosphamide; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Nitrogen Mustard Compounds; Phosphoramide Mustards
PubMed: 7448105
DOI: 10.1111/j.1365-2125.1980.tb01768.x -
Journal of Chromatography. B,... Jun 2021Highly polar ethanolamines (EAs), excreted in urine, are hydrolysis products of nitrogen mustards (NMs), which are prohibited by the Chemical Weapons Convention (CWC)....
Highly polar ethanolamines (EAs), excreted in urine, are hydrolysis products of nitrogen mustards (NMs), which are prohibited by the Chemical Weapons Convention (CWC). The methods established for biological matrices are essential for verification analysis of the CWC related chemicals. This paper describes a new liquid chromatography-tandem mass spectrometry (LC-MS/MS) method developed for qualitative and quantitative analysis of EAs, N-ethyldiethanolamine (EDEA), N-methyldiethanolamine (MDEA) and triethanolamine (TEAOH) from urine samples. After optimization of sample preparation and chromatographic conditions, the method was fully validated. Silica solid-phase extraction (SPE) cartridges and a porous graphite carbon (PGC) column were selected for validation studies. The method is linear from 5 to 500, 0.5 to 250, and 0.5 to 500 ng/mL for TEAOH, EDEA, and MDEA, respectively. It is also precise and accurate. A minimum sample amount of 0.5 mL urine was used. The limit of quantification using this approach was 0.4, 5.5, and 6.3 ng/mL for MDEA, EDEA and TEAOH, respectively. The combination of the PGC column and high pH eluents in analysis retained and separated the studied EAs. Retention times were 2.11, 2.56 and 2.98 min for MDEA, EDEA and TEAOH, respectively. The method is applicable for verification analysis of the CWC.
Topics: Chromatography, Liquid; Ethanolamines; Female; Humans; Hydrolysis; Linear Models; Male; Nitrogen Mustard Compounds; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry
PubMed: 34052559
DOI: 10.1016/j.jchromb.2021.122762