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PubMed1997

Hematopoietic toxicity and cell cycle perturbations induced by new DNA minor groove-alkylating agents.

Some new alkylating agents which bind to the minor groove of DNA and have sequence-specific patterns of alkylation have shown anti-neoplastic activity in pre-clinical systems. Two of them, carzelesin and tallimustine, are now in phase II. Considering the severe dose-limiting bone marrow toxicity of both these drugs in clinical use, it was of interest to investigate the mechanism of their myelotoxicity in a detailed pre-clinical study and compare it with a conventional alkylating agent, such as melphalan. The origin and progression of the myelotoxicity of carzelesin, tallimustine and melphalan were investigated comparatively in mice, combining data on bone marrow and peripheral blood cellularity with data on the proliferative activity of bone marrow cells, obtained by in vivo administration of bromodeoxyuridine. Significant differences were found between the hematopoietic response to the 3 drugs, though all caused severe leukopenia. Carzelesin induced a short-term increase in myeloid proliferative activity, which prevented the high leukocytopenia on day 3 observed with the other drugs. However, when this effect was exhausted, a second nadir was seen in peripheral blood, with a new wave of cell proliferation of all lineages in the bone marrow. Reconstruction of the lymphoid lineage was slow for all 3 drugs but particularly difficult with high-dose tallimustine. In general, the hematopoietic system response to tallimustine was dampened, with no overshoots, suggesting either lasting effects or extensive cytotoxicity from the early to late precursors of all lineages.

Animals↗
PubMed1993

The biology of alkylating-agent cellular injury.

Alkylating agents, such as nitrogen mustard, cyclophosphamide, and the nitrosoureas, have been used to treat many malignancies for more than 30 years. It is now clear that they are not only cytotoxic but also mutagenic and carcinogenic. The initial alkylation event, monoadduct formation on ring nitrogens or extra-cyclic oxygens of nucleotide bases, can result in chromosomal loss or single base mutation, both of which can lead to malignant transformation. The bone marrow is particularly sensitive to these events, and acute myelogenous leukemia is the most common malignancy caused by alkylating agents. Mechanisms of genetic damage and mutagenesis are discussed.

Alkylating Agents↗
PubMedDate not supplied

Alkylating agents and DNA polymerases.

Alkylating agents, for example nitrogen "mustards", are variably toxic, mutagenic, carcinogenic and teratogenic, but by mechanisms which have not been clearly established. In particular, the mechanisms both of their delayed toxic effects (which are primarily against dividing cells, in association with retardation of the rate of cell division, disruption of mitoses, and breakages and other abnormalities of chromosomes) and of their carcinogenic actions are not understood. The literature on the testing of thousands of analogues has demonstrated great variability of effects on the various cell biological phenomena, and no aspect of chemical structure or biochemical reactivity of these agents has been established as especially related to any particular effect. Here theories of the mechanisms of action of alkylating agents are reviewed and it is suggested that impairment of the functions of DNA polymerase complexes might contribute to some of the effects of alkylating agents. In particular, impairment of replicative fidelity of DNA during the S-phase could contribute to some of the mitotic and chromosomal effects, as well as to their carcinogenic and teratogenic potencies. Some aspects of testing the effects of alkylating agents on components of the DNA synthetic pathway are mentioned. Emphasis is given to consideration of the various relevant levels (conventional plasma/tissue; tissue/tumour cell cytoplasm; tumour cell cytoplasm/tumour cell nucleus and tumour nuclear karyoplasm/tumour chromatin] of the pharmacokinetics and pharmacodynamics of the agents and their metabolites.

Alkylating Agents↗
PubMed1977

Synthesis and biological action of two glucocorticoid alkylating agents.

Two alkylating glucocorticoids have been synthesized in order to test the possibility of alkylating glucocorticoid receptors. The title compounds are 9alpha-fluoro-11beta,16alpha,17alpha,21-tetrahydroxypregna-1,4-diene-3,20-dione 21-[bis(2-chloroethyl)carbamate] 16,17-acetonide (I) and 11beta,17alpha,21-trihydroxypregn-4-ene-3,20-dione 21-[bis(2-chloroethyl)carbamate] (II), prepared from triamcinolone acetonide and cortisol, respectively, through the reaction of the C-21 hydroxyl group with phosgene and di-2-chloroethylamine in the presence of triethylamine. Both compounds are biologically active as inhibitors of the growth of cultured mouse fibroblasts and are able to compete for the specific binding of radiolabeled triamcinolone acetonide to the L929 cell receptor. The bis(2-chloroethyl)carbamate moiety is capable of reacting with nucleophilic groups as evidenced by the colorimetric reaction with 4-(p-nitrobenzyl)pyridine. Both the interaction with the receptor and inhibition of cell growth by these two glucocorticoids are reversible.

Alkylating Agents↗
PubMed2002

Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen.

PURPOSE: To compare in a phase III study the safety and efficacy of fludarabine to that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. PATIENTS AND METHODS: Patients were randomized to fludarabine (25 mg/m(2) intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m(2) and vincristine 1.2 mg/m(2) both intravenously on day 1 and prednisone 40 mg/m(2) orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. RESULTS: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P =.72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P =.03) and TFS (15 months v 11 months; P =.02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P =.95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P =.008); no other differences in QoL were detected. CONCLUSION: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS.

Adult↗
PubMed1991

Synergistic cytotoxicity of different alkylating agents for epithelial ovarian cancer.

Alkylating agents have been used individually and in combination to treat epithelial ovarian carcinoma. In this study, the cytotoxicity of 7 alkylating agents has been measured using a serial dilution clonogenic assay. When individual agents were evaluated, markedly different activity was observed against several ovarian cancer cell lines. Among 4 cell lines tested, OVCA 432 was the most sensitive to cisplatin, thiotepa and melphalan. When alkylating agents were used in combination against OVCA 432, synergistic activity was observed with cisplatin and each of several other alkylating agents including thiotepa, melphalan, 4-hydroperoxycyclophosphamide (4HC) and carboplatin. The combination of cisplatin and thiotepa also exerted synergistic activity against the OVCA 420, 429 and 433 cell lines, but had only additive or subadditive activity against the NIH:OVCAR-3 cell line. Sequential treatment of tumor cell lines with the different alkylating agents was as effective as simultaneous treatment. Synergistic anti-tumor activity in cell culture is consistent with clinical observations that alkylating agents in combination appear more effective than single agents for treatment of advanced epithelial ovarian cancer. In addition, our study suggests that cisplatin in combination with thiotepa, 4HC or melphalan might prove useful for high-dose therapy with autologous bone-marrow support.

Alkylating Agents↗
PubMed2000

Clinical applications of quinone-containing alkylating agents.

Quinone-containing alkylating agents are a class of chemical agents that have received considerable interest as anticancer drugs. These agents contain a quinone moiety that can be reduced and an alkylating group that can form covalent bonds with a variety of cellular components. The oxidation state of the quinone element can modulate the activity of the alkylating element, and reduction of the quinone is required for activation of the alkylating activity of many of these agents. The quinone element may also contribute to the cytotoxic activity of quinone-containing alkylating agents through the formation of reactive oxygen species during redox cycling. The natural product, mitomycin C, has been the most widely used quinone-containing alkylating agent in the clinic, but other quinone-containing alkylating agents like porfiromycin, diaziquone, carbazilquinone, triaziquone and EO9 have also been used in the clinic for the treatment of cancer. In addition, many other quinone-containing alkylating agents have been tested in preclinical studies and the development of new agents is being actively pursued. This chapter describes the current and past clinical uses of these agents in the treatment of cancer and discusses new agents that are currently in clinical trials.

Antibiotics, Antineoplastic↗
PubMed1990

Replication-linked histone acetylation in rat liver tissue is sensitive to alkylating agents.

The effect of alkylating agents on histone acetyltransferase (EC 2.3.1.48) activity and thymidine incorporation was investigated in benign and malignant proliferating rat liver tissue and compared with the effect in normal non-proliferating rat liver tissue. In both, benign and malignant proliferating tissue, but not in quiescent tissue, the histone acetylation is depressed by alkylating agents and this depression correlates with the inhibition of the thymidine incorporation. This effect suggests that the depression of the replication associated histone acetylation may be an important factor for the antiproliferative activity of alkylating agents.

Acetylation↗
PubMed1994

3T3 NIH murine fibroblasts and B78 murine melanoma cells expressing the Escherichia coli N3-methyladenine-DNA glycosylase I do not become resistant to alkylating agents.

The role of alkylation of the N3 position of adenine in the cytotoxicity of alkylating agents in mammalian cells is still undefined. By co-transfecting NIH3T3 murine fibroblast and murine B78 H1 melanoma cells with pSG5tag and pSV2neo, we obtained clones expressing the mRNA of the bacterial tag gene coding for N3-methyladenine-DNA glycosylase I (Gly I), which specifically repairs N3-methyladenine. The levels of Gly I were 400 times higher in NIH3T3 pSG5tag (clone 3.9.4) and 12-33 times higher in B78 H1 tag clones (2A4, 2A6, 2C3 and 2D1) than in the respective control cells. The sensitivity to alkylating agents was evaluated in tag-expressing cells in comparison with pSG5, pSV2neo co-transfected control cells. As regards the cytotoxic activity of methylating agents (N-methylnitrosourea, N-methyl-N'-nitro-N-nitrosoguanidine, dimethylsulfate and temozolomide) and other alkylators with different structure and different interactions with DNA such as CC-1065 and FCE-24517 (minor groove binders known to bind to N3 of adenine), 4-[bis(2-chloroethyl)amino]-L-phenylalanine and cis-diamminedichloroplatinum II, cytotoxicity was the same for tag-expressing and non-expressing cells. These results suggest that the increased expression of N3-methyladenine-DNA glycosylase is not necessarily a crucial mechanism for the resistance of cells to alkylating agents.

3T3 Cells↗
PubMed1978

Pathways of mutagenesis and repair in Escherichia coli exposed to low levels of simple alkylating agents.

Mutagenesis by simple alkylating agents is thought to occur by either a lexA+-dependent process called error-prone repair or a lex-independent process often attributed to mispairing during replication. We show here that error-prone repair is responsible for the majority of mutants formed after a large dose of alkylating agent, but it is unlikely that it contributes significantly to mutagenesis during exposure to low concentrations of these chemicals. The mutagenicity of these low doses of alkylating agent is reduced by a repair system constitutively present in lexA+ cells but absent in lexA mutants. This system reduces mutagenesis until a second error-free system, called the adaptive responses, can be induced [P. Jeggo, M. Defais, L. Samson, and P. Schendel, Mol. Gen. Genet, 157:1-9, 1977; L. Samson and J. Cairns, Nature (London) 267:281-283, 1977]. The adaptive response is capable of dealing with a much larger amount of alkylation damage than the constitutive system and, when induced, appears to be able to reduce mutagenesis by both decreasing the number of sites available for mutagenesis and delaying the induction of error-prone repair enzymes. Finally, we discuss a model of chemically induced mutagenesis based on these findings which maintains that the observed mutation frequency is dependent on a "race" between these two error-free systems and the two mutagenic pathways.

Alkylating Agents↗
PubMedDate not supplied

Synergism between alkylating agent and cis-platin with moderate local hyperthermia: the effect of multidrug chemotherapy in an animal system.

The combined effect of multidrug chemotherapy given in combination with hyperthermia was investigated using early-generation isotransplants of a spontaneous fibrosarcoma, FSa-II in C3Hf/Sed mice. Combinations of various types of chemotherapeutic agents, including alkylating agents, cyclophosphamide (CY) and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU); antibiotics, bleomycin (BLM) and mitomycin C (MMC); an antimetabolite, 5-fluorouracil (5FU); and a platinum complex, cis-diamminedichloroplatinum(II) (cDDP), were examined using the tumour growth (TG) time assay. Simultaneously, the effect of glucose on the response to thermochemotherapy was investigated. Graded doses of the multidrugs were given i.p. immediately before hyperthermia with or without a glucose dose of 5 g/kg given i.p. 60 min before hyperthermia. Hyperthermia was given by immersing the tumour-bearing murine feet into a water bath set at 41.5 +/- 0.05 degrees C for 60 min. Dose-response curves were obtained between the TG time and drug dose. The thermal enhancement ratio (TER) was expressed as a ratio of the slope of the dose-response curve obtained at 41.5 degrees C to that obtained at room temperature. To evaluate normal tissue damage, the number of white blood cells (WBC) was counted from a day before treatment to the 21st day after treatment. A substantial thermal enhancement of the anti-tumour effect was observed in all five multidrug regimens tested. Glucose administered prior to thermochemotherapy further enhanced the antitumour effect. The TER was largest for the combination of CY+cDDP (TER was 5 without glucose). The second largest TER was obtained for a combination of CY+cDDP+MMC (TER was 4.1 without glucose and 6.5 with glucose). The antitumour effects of these two combinations were synergistic at a test elevated temperature only. No synergistic effect was found at room temperature for any of the drug combinations tested. The smaller TERs were observed in the treatment regimens that included 5FU. In general, a decrease in the number of WBC following multidrug chemotherapy was slightly less than that following the individual drugs.

Alkylating Agents↗
PubMed2000

The human cyclin B1 protein modulates sensitivity of DNA mismatch repair deficient prostate cancer cell lines to alkylating agents.

DNA damage caused by alkylating agents results in a G2 checkpoint arrest. DNA mismatch repair (MMR) deficient cells are resistant to killing by alkylating agents and are unable to arrest the cell cycle in G2 phase after alkylation damage. We investigated the response of two MMR-deficient prostate cancer cell lines DU145 and LNCaP to the alkylating agent MNNG. Our studies reveal that DU145 cancer cells are more sensitive to killing by MNNG than LNCaP. Investigation of the underlying reasons for lower resistance revealed that the DU145 cells contain low endogenous levels of cyclin B1. We provide direct evidence that the endogenous level of cyclin B1 modulates the sensitivity of MMR-deficient prostate cancer cells to alkylating agents.

Alkylating Agents↗
PubMed1995

Effect of alkyl-N-purine DNA glycosylase overexpression on cellular resistance to bifunctional alkylating agents.

Increased activity of alkyl-N-purine DNA glycosylase (ANPG; a.k.a. N3-methyladenine DNA glycosylase) has been correlated with resistance to both chloroethylnitrosoureas and nitrogen mustards. Also, overexpression of the human glycosylase in Escherichia coli results in resistance to alkylating agents. To determine how overexpression of the protein affects resistance to these bifunctional alkylating agents in mammalian cells, wild-type CHO-AA8 cells were transfected with an expression construct containing the human ANPG cDNA. Several clonally isolated lines that expressed increasing levels of glycosylase activity were selected. None of these lines displayed increased resistance to either bis-chloroethylnitrosourea or melphalan. To determine how overexpression of this protein affects cells in the absence of nucleotide excision repair, the mutant CHO-UV20 cell line was transfected with the same expression construct. This cell line lacks functional ERCC-1 protein and displays extreme hypersensitivity to bifunctional alkylating agents. Again, none of the UV20 transfectants displayed increased resistance. The results of these experiments indicate that unlike E. coli, overexpression of the glycosylase alone is not sufficient to confer resistance to bifunctional alkylating agents in this system. Structural differences between mammalian cells and E. coli may explain the interesting result that a mammalian gene can confer drug resistance in E. coli but not in mammalian cells.

Alkylating Agents↗
PubMed1992

A straight correlation between mutagenic activity and beta-galactosidase activity induced by monofunctional alkylating agents.

Eight monofunctional alkylating agents were examined for their ability to induce mutation in Salmonella typhimurium. The assay was carried out in S. typhimurium TA100 with the preincubation method. The SN1-type agents were more mutagenic than the SN2-type ones; besides, methylating agents exerted more mutagenic activity than ethylating ones. Those responses in the reversion assay were quite similar to the results obtained previously with the beta-galactosidase assay in Escherichia coli CSH26/pMCP1000 (alkA'-lacZ') as to the induction of the adaptive response. A good correlation was found between mutagenic potency in the reverse mutation assay and inducing potency in the beta-galactosidase assay.

Alkylating Agents↗