The selectivity of action of alkylating agents and drug resistance—III
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Chlorambucil
Melphalan
Nitrogen mustard
Chlormethine (Nitrogen mustard) in small doses proved to have immunopotentiating and anti-inflammatory activities. The influence of two nitrogen mustard derivatives : chlorambucil (1 or 10 micrograms/kg p.o.) and cyclophosphamide (0.03 or 0.3 mg/kg i.v.) as well as busulphan (0.5 or 5 micrograms/kg p.o.)--the agent of ++alkylating cytostatic group were investigated in rabbits. Whole blood count, the number of T and B lymphocytes, serum IgG level, phagocytic and microbicidal activities of neutrophils and the plasma level of free glucocorticoids were estimated. The drugs were used in the doses 10-100 times lower than cytostatic ones. Moreover, the ability of alkylating drugs to enhance or to suppress the changes evoked by lipopolysaccharide of E. coli in examined parameters was assessed. The results were compared with chlormethine data obtained previously. None of two nitrogen mustard derivatives (chlorambucil or cyclophosphamide) in the doses many times lower than cytostatic ones, exhibited an immunostimulating and adjuvant properties characteristic of chlormethine. Such properties did not demonstrate small doses of busulphan, another compound of alkylating drugs.
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Chlorambucil
Nitrogen mustard
Melphalan
Prednisolone
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We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10–14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.
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Chlorambucil
Melphalan
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The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug. HN2 was considerably more cytotoxic than melphalan as determined by inhibition of colony formation. Immediately following exposure to HN2 maximum levels of DNA cross-links were found. Melphalan, in contrast, caused a protracted induction of DNA cross-links with maximum levels obtained 6-12 h following drug exposure. HN2 induced approximately 13 times higher peak levels of DNA cross-links compared to equal concentrations of melphalan. Removal of DNA cross-links following exposure to both drugs followed an exponential time course. The rate of removal of HN2-induced DNA cross-links was, however, 1.5-2.4 times more rapid than that of melphalan-induced cross-links. A strong correlation was obtained between the cytotoxicity of both drugs and the total area under the curve for DNA interstrand cross-links, indicating that both the initial induction of as well as the rate of removal of DNA interstrand cross-links are important for the cytotoxic effects of bifunctional alkylating agents.
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The formation of DNA cross-links is thought to represent the lethal lesion following exposure of cells to bifunctional alkylating agents. Since differences in rates of formation and repair of cross-links may explain differences in activity of these agents, we have studied these events following exposure of L1210 cells to nitrogen mustard (HN2) and melphalan. With the technique of alkaline elution, it was possible to measure cross-linking at doses that result in relatively little cell kill. Following a 30-min exposure to HN2, DNA cross-links increased for 1 to 2 hr and were then removed by a process that was virtually complete in 24 hr. In contrast, following a 30-min exposure to melphalan, cross-link formation increased for 12 hr and removal was much slower than it was for HN2. Comparison of cell survival with cross-linking kinetics suggests that persistence of the cross-links with time is an important factor in determining lethality.
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CHLORAMBUCIL (P-[di-2-chloroethylamino]-phenylbutyric acid, or CB 1348) is an analogue of nitrogen mustard that may be administered orally. There have been several reports attesting to its usefulness in the treatment of patients with lymphoma and chronic lymphocytic leukemia.1 2 3 4 5 A considerable experience has been accumulated at the Memorial Center for Cancer and Allied Diseases with nitrogen mustard6 and triethylene melamine,7 and it was against this background that the study of the use of chlorambucil was made.To evaluate the use of chlorambucil, particular attention was paid to specific points of administration and response such as the value of maintenance therapy, combination therapy . . .
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Chlorambucil
Nitrogen mustard
Sulfur mustard
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