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PubMed1996

Analysis of mitotic recombination induced by several mono- and bifunctional alkylating agents in the Drosophila wing-spot test.

Mitotic recombination induced by six alkylating agents has been studied in the wing-spot test of Drosophila melanogaster. The model mutagens chosen have different models of action at the DNA level. These are: the direct-acting small alkylating agent methylmethanesulfonate (MMS), the small promutagens N-dimethylnitrosamine (DMN) and N-diethylnitrosamine (DEN), the bifunctional cross-linking alkylating agents mitomycin C (MMC), chlorambucil (CLA) and monocrotaline (MCT). Flies of the standard cross (flr3 / TM3, Bds females and mwh males) were used to produce the larvae to be treated. Three-day old Drosophila larvae were exposed by chronic feeding for 48 h to three different concentrations of all six alkylating agents. Acute feeding for only 2 h was used in addition with DEN and MMC. Wings of the marker-heterozygous (mwh+ / + flr3) as well as of the balancer-heterozygous (mwh+ / TM3, Bds) progeny were analysed. The ranking of the compounds with respect to their genotoxic potency, based on mwh clone formation frequency in marker-heterozygous wings was: MMS > MNC > DMN > CLA approximately MCT > DEN. The ranking with respect to the induction of twin spots, which are produced by mitotic recombination exclusively, was: MMS > DMN > MMC > MCT > CLA > DEN. The quantitative determination of recombinagenic activity, based on mwh clone formation frequencies obtained in both types of wings, gave the following values: MMS, 93%; MCT, 87%; CLA, 80%; MMC, 73%; DMN, 67%; DEN, 22%. A clear relationship exists between the extent of N-alkylation of DNA and the efficiency of the monofunctional agents MMS and DMN as well of the bifunctional agents MCT, CLA and MMC to induce mitotic recombination. This contrasts with the ethylation of base oxygen atoms and the resulting lower efficiency of DEN to produce mitotic recombination.

Alkylating Agents↗

PubMed1998

Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes.

Alkylation of DNA at the O6-position of guanine is one of the most critical events leading to mutation, cancer, and cell death. The enzyme O6-methylguanine-DNA methyltransferase repairs O6-methylguanine as well as a minor methylated base, O4-methylthymine, in DNA. Mouse lines deficient in the methyltransferase (MGMT) gene are hypersensitive to both the killing and to the tumorigenic effects of alkylating agents. We now show that these dual effects of an alkylating agent can be dissociated by introduction of an additional defect in mismatch repair. Mice with mutations in both alleles of the MGMT gene and one of the mismatch repair genes, MLH1, are as resistant to methylnitrosourea (MNU) as are wild-type mice, in terms of survival, but do have numerous tumors after receiving MNU. In contrast to MGMT-/- MLH1(+/+) mice with decrease in size of the thymus and hypocellular bone marrow after MNU administration, no conspicuous change was found in MGMT-/- MLH1(-/-) mice treated in the same manner. Thus, killing and tumorigenic effects of an alkylating agent can be dissociated by preventing mismatch repair pathways.

Adaptor Proteins, Signal Transducing↗

PubMed1989

Influence of schedule on alkylating agent cytotoxicity in vitro and in vivo.

High dose, multiple alkylating agent chemotherapy is being employed in conjunction with autologous marrow transplantation in the clinic. We have investigated the scheduling of several alkylating drugs in an effort to optimize their antitumor effects. In vitro modeling of "continuous" (up to 72 h) versus "bolus" (1 h) exposure in MCF-7 cells showed that for N,N',N"-triethylenethiophosphoramide (thiotEPA), cis-diamminedichloroplatinum(II) (CDDP), 4-hydroperoxycyclophosphamide, carboplatin, and L-phenylalanine mustard (L-PAM) "continuous" exposure yielded essentially the same killing kinetics as "bolus" exposure. For N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU), however, even with fresh drug additions every 30 min, "bolus" exposure produced superior cytotoxicity. In vivo modeling of "continuous" (three i.p. injections over 9 h) versus "bolus" (single dose) administration of the alkylating agents cyclophosphamide, BCNU, thiotEPA, melphalan, CDDP, and carboplatin was conducted in mice bearing EMT6 tumors, and tumor cell killing as measured by tumor cell survival in vitro was compared with killing of bone marrow (CFU-GM) measured in culture as a representative sensitive normal tissue. With cyclophosphamide there was a considerable increase in the therapeutic index (killing of tumor cells/killing of CFU-GMs) when the same total dose of drug was administered in multiple injections versus a single injection. For BCNU and thiotEPA, smaller increases in therapeutic index were observed. With L-PAM and CDDP, some advantage to multiple versus single dose administration was observed, and for carboplatin a decrease in the therapeutic index was seen. In conclusion, for all six alkylating agents examined, the multiple dose schedule was at least as effective against the tumor as the single dose schedule at all dose levels.

Adenocarcinoma↗

PubMed2003

Human-yeast chimeric repair protein protects mammalian cells against alkylating agents: enhancement of MGMT protection.

Chemotherapeutic DNA alkylating agents are common weapons employed to fight both pediatric and adult cancers. In addition to cancerous cells, nontarget tissues are subjected to the cytotoxicity of these agents, and dose-limiting toxicity in the form of myelosuppression is a frequent result of treatment. One approach to prevent myelosuppression that results from the use of chemotherapeutic agents is to increase the levels of DNA repair proteins in bone marrow cells. Here we report our second successful attempt to create a fusion protein that possesses both direct reversal and base excision repair pathway DNA repair activities. The chimeric protein is composed of the human O(6)-Methylguanine-DNA Methyltransferase (MGMT) and the yeast Apn1 proteins and retains both MGMT and AP endonuclease activities as determined by biochemical analysis. We have also demonstrated that the chimeric protein is able to protect mammalian cells from the DNA alkylating agents 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) and methyl methanesulfonate (MMS). The protection by the chimeric protein against BCNU is even greater than MGMT alone, which has potential translational significance given that MGMT is currently in clinical trials. Additionally, we show that the chimeric MGMT-Apn1 protein can protect mammalian cells from dual treatments of BCNU and MMS and that this effect is greater than that provided by MGMT alone. The data support our previous finding that a protein with multiple DNA repair activities can be constructed and that this and other constructs may play an important clinical role in guarding against dose-limiting effects of chemotherapy, particularly in situations of multiple drug use.

Alkylating Agents↗

PubMed1981

[Repair of DNA-protein cross-links induced by antineoplastic alkylating agents].

The bifunctional and antitumor alkylating agents embichin and its aromatic derivatives sarcolysin and chlorfenacyl remarkably differ in DNA-protein cross-links induction in Chinese hamster cell cultures in vitro. The differences involve the concentration necessary for cross-linkage, the time of cross-links emergence, and their reparation. Since all three compounds have the same alkylating group, it is obvious that the differences seen in the cross-linkage arise from the structure of aromatic groupings introduced into the molecule.

Alkylating Agents↗

PubMed1993

Antitumor alkylating agents: in vitro cross-resistance and collateral sensitivity studies.

Cell lines resistant to five antitumor alkylating agents (CDDP, PAM, 4-HC, HN2, and BCNU) were developed from five parental human tumor lines representative of solid tumors with a range of sensitivities to antitumor alkylating agents. The parental cell lines were SCC-25 squamous carcinoma of the head and neck, MCF-7 breast carcinoma, SW2 small-cell lung cancer, SL6 non-small-cell lung carcinoma, and G3361 melanoma. Survival curves using colony formation as the endpoint were generated for each of the 25 cell lines to each of the five alkylating agents. Comparison of the drug concentrations that reduced the survival of the alkylating agent-resistant cell lines by 90% (IC90 values) with the IC90 values obtained for the corresponding parental cell lines was used as a measure of the resistance/sensitivity of the alkylating agent-resistant lines to each drug tested. Although cross-resistance among the alkylating agents was generally uncommon, several patterns of response emerged. Cross-resistance occurred in 27 of the 105 determinations and occurred most frequently in the cell lines in which resistance was developed to PAM (57%) or BCNU (38%). Cross-resistance to HN2 occurred most frequently. Collateral sensitivity was equally as common, occurring in 25 of the 105 determinations. Collateral sensitivity occurred most frequently in the cell lines made resistant to 4-HC. The 4-HC-resistant cell lines were most frequently collaterally sensitive to PAM and to BCNU. Cross-resistance developed most frequently in the MCF-7 breast carcinoma and SCC-25 squamous-cell carcinoma cell lines, whereas collateral sensitivity developed most frequently in the SW2 small-cell lung cancer line and the G3361 melanoma cell line and least frequently in the MCF-7 breast carcinoma cell line and the SL6 non-small-cell lung cancer cell line. The implication of these findings for the development of strategies for clinical treatment are discussed.

Alkylating Agents↗

PubMed1982

Genetic mapping of ada and adc mutations affecting the adaptive response of Escherichia coli to alkylating agents.

The adaptive response to alkylating agents is an inducible repair system which protects Escherichia coli against the mutagenicity and toxicity of these agents. Four mutations, ada-3, ada-5, ada-6, and adc-1, which confer differing phenotypes as regards this response, were shown to be cotransducible with gyrA, and were located at 47 min on the E. coli genetic map. A mutation already shown on the map at 47 min as tag (B. J. Bachmann and K. B. Low, Microbiol. Rev. 44:1--56, 1980; Karran et al., J. Mol. Biol. 140:101--127, 1980) is now known to be an ada mutation (G. Evensen and E. Seeberg, personal communication).

Alkylating Agents↗

PubMed1992

Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies.

Although the alkylating agents were amongst the first non-hormonal compounds to be shown to be active against malignant cells they still rank as some of the most valuable cytotoxic drugs available for the treatment of patients with leukaemia and lymphoma. Melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide and the nitrosoureas are all members of this class of drug, which are believed to exert their cytotoxic effects through the covalent linkage of alkyl groups to DNA. In the first report describing the use of alkylating agents in clinical practice the problem of drug resistance was recognised. In spite of this there is still comparatively little known about the mechanisms underlying the development of resistance as it occurs in patients. Studies using animal models and cell lines have suggested that both cellular and extracellular factors may be involved, but the precise relevance of these to the clinical setting is unclear. A greater understanding of the mode of action and mechanisms of resistance to alkylating agents should enable the development of modulators capable of the restoration of sensitivity to resistant cells, and the more effective use of these well established drugs.

Alkylating Agents↗

PubMedDate not supplied

Mitomycin-C as a prototype bioreductive alkylating agent: in vitro studies of metabolism and cytotoxicity.

The bioreductive alkylating agents are prodrugs for chemotherapy which are enzymatically reduced within cells to species capable of alkylating biological molecules and producing cytotoxic damage. Studies presented in this report show that MIT-C has the characteristics expected of a bioreductive alkylating agent: activation to alkylating species occurs more readily under hypoxic conditions and the drug is selectively cytotoxic to hypoxic cells.

Alkylating Agents↗

PubMed1987

Embryotoxicity induced by alkylating agents. Some methodological aspects of DNA alkylation studies in murine embryos using ethylmethanesulfonate.

Synthesis and spectroscopic analysis of some alkylated DNA purine bases are described. HPLC separation methods are developed for the determination of DNA alkylation rates in mammalian embryonic tissues. Following treatment of pregnant mice with the ethylating agent ethylmethanesulfonate (EMS), an appreciable amount of alkylation (ethylation and methylation) was found in the nuclear DNA of the embryos during organogenesis. The results are discussed in context of our thesis that a certain amount of DNA alkylation in the embryos is correlated to the teratogenic potential of alkylating agents.

Adenine↗

PubMed1979

Concentration-dependent mutation by alkylating agents in human lymphoblasts and Salmonella typhimurium: N-methyl-N-nitrosourethane and beta-propiolactone.

The toxic and mutagenic effects of the alkylating agents N-methyl-N-nitrosourethane (MNUT) and beta-propiolactone (BPL) were quantitatively measured in human lymphoblasts and Salmonella typhimurium. Forward mutation to 6-thioguanine resistance was measured in the human lymphoblasts, and forward mutation to 8-azaguanine resistance was measured in the bacterial cells after equigenerational (1.5 doubling times) exposures. In both systems, the induced mutant fraction rose linearly as a function of concentration for BPL and was biphasic for MNUT. The responses of the two assay systems to eight alkylating agents were compared. The exposure of the cells to each alkylating agent was calculated as exposure concentration multiplied by the time of exposure, and allowance was made for the decomposition of the alkylating agents during exposure (integral exposure). Human cells were 2.5--13 times more sensitive than was S. typhimurium to the alkylating agents methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, methylnitrosourea, and MNUT. S. typhimurium cells were three times more sensitive to butyl methanesulfonate and 25 times more sensitive to BPL than were human cells.

Alkylating Agents↗

PubMed1991

Lonidamine as a modulator of alkylating agent activity in vitro and in vivo.

We are searching for relatively nontoxic compounds that can positively modulate the efficacy of antitumor alkylating agents. Lonidamine inhibits cellular energy metabolism and could potentially increase damage by alkylating agents if cellular defenses are energy requiring. Exposure of cells to lonidamine (500 microM) for 2 h under hypoxic conditions followed by 1-h exposures to lonidamine plus alkylating agents under normally oxygenated conditions in vitro significantly increased the cell kill achieved by cis-diamminedichloroplatinum(II) (CDDP) approximately 5-fold and by D-tetraplatin approximately 10-fold at 90% inhibitory concentration in MCF-7/CDDP (CDDP-resistant) cells. Carboplatin cytotoxicity, however, was little changed. In the MCF-7 parent cell line, treatment with lonidamine increased CDDP cytotoxicity by approximately 10-fold, D-tetraplatin by approximately 10-fold, and carboplatin by approximately 8-fold at the 90% inhibitory concentration. For L-phenylalanine mustard (melphalan), N,N',N"-triethylenethiophosphoramide (thiotepa), and N,N'-bis(2-chloroethyl)-N-nitrosourea, little resistance was evident in the MCF-7/CDDP lines compared with the parent line. Treatment with lonidamine increased the cytotoxicity of each drug by 1.5- to 3-fold in both cell lines. When exposure to lonidamine was extended to 24 h before and 12 h after drug exposure in MCF-7 normally oxygenated cultures, CDDP (250 microM) cytotoxicity was increased by approximately 100-fold, but melphalan cytotoxicity was increased only 2- to 3-fold over the concentration range tested. In the FSaIIC murine fibrosarcoma tumor system, five i.p. injections of 50 mg/kg of lonidamine over 36 h increased the tumor cell kill by CDDP and carboplatin approximately 2- to 3-fold over the dose range tested when the platinum complexes were given i.p. immediately after the third lonidamine injection. When cyclophosphamide and thiotepa were given in the same schedule, 10-fold increases in tumor cell killing were evident on tumor excision assay over the dosage ranges. The increase in bone marrow toxicity caused by lonidamine in addition to the alkylating agents was less than for tumor cells. Finally, in the EMT6 murine mammary carcinoma, use of lonidamine at 500 mg/kg twice daily along with CDDP, carboplatin, thiotepa, and cyclophosphamide significantly increased tumor growth delays by approximately 1.6- to 3.0-fold. The results suggest that lonidamine can positively modulate antitumor alkylating agent cytotoxicity and may be a clinically useful adjunctive therapy with these drugs.

Animals↗

PubMed1977

Acute leukemia after alkylating-agent therapy of ovarian cancer.

To estimate the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attribute to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease.

Acute Disease↗

PubMed1997

The relationship of a novel drug-resistant phenotype in C3H10T1/2 cells selected with alkylating agents to neoplastic transformation and ATP metabolism.

We investigated the resistance to alkylating agents in parental, drug-selected and neoplastically transformed C3H10T1/2 (10T1/2) murine fibroblasts. Similar levels of resistance to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were observed in cells selected for resistance to MNNG or 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) as well as in cells transformed by a single treatment with MNNG. Surprisingly, neither the levels of O6-alkylguanine-DNA alkyltransferase (AT) nor glutathione-S-transferase (GST) were altered in drug-resistant cells. In contrast, changes in ATP metabolism were observed in both transformed and MNNG-selected cells after treatment with MNNG. Specifically, 3 h after treatment with 5 microg/ml MNNG, ATP levels decreased by 85% and 74% in MNNG-selected and transformed cells, respectively, compared to only a 28% decrease in parental cells. Therefore, rather than contributing to cell sensitivity to alkylating agents, the ability to rapidly utilize ATP and tolerate resulting decreases in ATP levels may in some cases play a role in protection from the cytotoxic effects of alkylating agents.

Adenosine Triphosphate↗

PubMed1976

[Interaction of electrophilic alkylating agents with nucleophilic sites of mitochondria].

The electrophilic alkylating agents having different numbers of electrophilic groups with nucleophilic sites of mitochondria were studied. Bifunctional compounds were found to modify the structure of mitochondria so that some of the sulfhydryl groups become inaccessible for titrating ions of Ag+. Monofunctional agents caused no changes in the number of determinable sulfhydryl groups and prevented the effect of bifunctional compounds. The linkage formed between the electrophilic residue and the nucleophilic site is stable in the absence of electron transport. During the transport of electrons in the respiratory chain the linkage becomes labile and the electrophilic residue chips off. A scheme of interaction of electrophilic alkylating agents with nucleophilic sites of mitochondria is proposed.

Alkylating Agents↗

PubMed1992

Enhancement of alkylating agent activity by SR-4233 in the FSaIIC murine fibrosarcoma.

BACKGROUND: The most commonly used antineoplastic drugs are more cytotoxic toward normally oxygenated tumor cells than toward hypoxic tumor cells. PURPOSE AND METHODS: To examine the ability of SR-4233, a new cytotoxic agent, to overcome the resistance of hypoxic tumor cells to antitumor alkylating agents, we tested the cytotoxic effect of SR-4233 alone and in combination with varying doses of cisplatin (CDDP), cyclophosphamide (CPM), carmustine (BCNU), or melphalan (L-PAM) on tumor cells and bone marrow cells isolated from C3H/FeJ mice bearing the FSaIIC fibrosarcoma. RESULTS: When SR-4233 alone was given, tumor cell killing was limited. When SR-4233 was administered just before single-dose treatment with CDDP, CPM, BCNU, or L-PAM, however, marked dose enhancement leading to increased cytotoxic effects on tumor cells and on bone marrow cells was observed. Similar experiments with tumor cell subpopulations, selected by Hoechst 33342 dye diffusion, confirmed that while cytotoxicity to both bright (oxygenated) and dim (hypoxic) cells was increased by combining each alkylating agent with SR-4233, the enhancement of the effect was relatively greater in the subpopulation of dim cells. The delay in the growth of tumors in animals treated with the combination of SR-4233 and CDDP, CPM, or L-PAM was 1.6-fold to 5.3-fold greater than that in animals treated with each alkylating agent alone. CONCLUSION: Our results suggest that SR-4233 may have the potential to improve the clinical efficacy of commonly used antitumor alkylating agents.

Alkylating Agents↗

PubMed1981

Fractionated dose studies with X-rays and various alkylating agents in P388 mouse lymphoma cells.

The fractionated dose technique has been used in P388F cells to examine the effects of X-rays and four alkylating agents on survival and induction of 5-iodo-2-deoxyuridine (IudR) resistant variants. Fractionation intervals up to 5 1/2 h were used for X-rays and for the alkylating agents up to 192 h. Fractionation of the X-ray dose resulted in a sparing effect for survival and variant induction. A sparing effect was also observed for survival after treatment with alkylating agents. However, variant frequencies were observed as large as or greater than those produced by the full doses of alkylating agents. For such agents this would suggest that survival and variant induction are independent events. Differences in the effects of X-rays and alkylating agents cannot be explained by differences in growth rate or the recovery of viability after treatment.

Alkylating Agents↗

PubMed1993

Cellular pharmacology of quinone bioreductive alkylating agents.

The cellular pharmacology of the mitomycin bioreductive alkylating agents is complex. This reflects in part the chemical characteristics of these quinones, which have multiple sites of reactivity and the capacity to produce a large number of different lesions of biological importance. Moreover, at least six different enzymes are capable of activating these compounds; the nature of the active species and the resultant biological lesions can vary with the activating enzyme. The relative activities of these reductases vary in different cell lines and can be modulated by pH and oxygenation. The effects of a quinone bioreductive alkylating agent therefore depend upon both the cell line and the microenvironment. DNA damage appears to be critical to the cytotoxic effects of these compounds. Both monoadducts and bis-adducts (forming interstrand and intrastrand cross-links) have been identified in DNA from drug-treated cells. The pattern of adduct formation varies with the compound and the environment. Alkaline elution studies suggest a correlation between DNA cross-linking and cytotoxicity, both in air and in hypoxia. The rate of production of oxygen radicals and the importance of radical reactions in producing cytotoxic damage vary for different quinones and for different environments. While the potency of the bioreductive quinones varies with their redox potential, the direction and magnitude of the oxic/hypoxic differential cannot yet be predicted from the structures.

Alkylating Agents↗