Biomedical subjects

A Begleiter

Publications and source records attributed to A Begleiter.

At least 37 records · Page 2Linked to original sources

PubMed1995

Comparison of antitumor activities of 2-chlorodeoxyadenosine and 9-beta-arabinosyl-2-fluoroadenine in chronic lymphocytic leukemia and marrow cells in vitro.

The in vitro antitumor activities of the nucleoside analogs, 2-chlorodeoxyadenosine (CdA) and 9-beta-arabinosyl-2-fluoroadenine monophosphate (Flu), and the alkylating agent, chlorambucil (CLB), were compared in leukemic cells from 28 patients with chronic lymphocytic leukemia (CLL). On a molar basis, the median sensitivities of the cells to these agents were CLB > CdA > Flu. CLL cells from 90% of the patients had similar relative orders of sensitivities to CdA and Flu, while cells from 10% of the patients showed differential sensitivities to these agents. There was no relationship between the sensitivities of the cells to the nucleoside analogs and sensitivity to CLB. CdA and CLB produced similar toxicities to human marrow progenitor cells in vitro, while Flu was less toxic to these cells. An 18 h exposure to CdA produced significantly greater cell kill of both CLL and marrow progenitor cells than an equivalent 2 h treatment; however, the difference in cytotoxicity was greater for the tumor cells resulting in a higher therapeutic index with the 18 h treatment. The intracellular accumulation of drug varied 5-fold for CdA, with the major metabolite being CdAMP, and 15-fold for Flu, with the major metabolite being F-ara-ATP. However, the accumulation of CdA, Flu or their metabolites did not predict for drug sensitivity. These studies suggest that CdA and Flu cross-resistance cannot be assumed in all CLL patients. The therapeutic effectiveness of CdA may be enhanced by use of a prolonged, low-dose drug regimen.

Antineoplastic Agents↗

PubMed1994

Activity of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin in sensitive and resistant L5178Y lymphoblasts in vitro.

An L5178Y murine lymphoblast cell line resistant to 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin (MRA-CN), L5178Y/MRA-CN, was isolated and characterized. L5178Y/MRA-CN cells were 9.6-fold resistant to MRA-CN compared with parental cells. The resistant cell line also displayed 2-fold resistance to 3'-(4-morpholinyl)-3'-deaminoadriamycin but was not cross-resistant to Adriamycin or chlorambucil. Uptake of MRA-CN was slightly reduced in the resistant cells compared to sensitive cells, but the distribution of the drug within the cells was unchanged. DNA interstrand cross-linking by MRA-CN was not significantly different in the sensitive and resistant cell lines, but MRA-CN was slightly less effective in inhibiting both DNA and RNA synthesis in L5178Y/MRA-CN cells compared with parental cells. NADPH cytochrome P-450 reductase activity was increased in L5178Y/MRA-CN cells compared to parental cells, while the activity of DT-diaphorase was decreased in the resistant cells. The levels of glutathione and glutathione S-transferase activity were increased in the resistant cells compared to sensitive cells; however, pretreatment of L5178Y/MRA-CN cells with buthionine sulfoximine to reduce the glutathione level did not reverse the resistance of these cells to MRA-CN. MRA-CN induced DNA fragmentation that was characteristic of apoptosis in both L5178Y and L5178Y/MRA-CN cells at equitoxic drug concentrations. However, apoptosis occurred more rapidly in L5178Y/MRA-CN cells compared with parental cells. Thus, MRA-CN induces apoptosis in L5178Y cells, and this effect may be important for the anti-tumor activity of this agent. In contrast, DNA interstrand cross-linking does not appear to be the primary mechanism responsible for the cytotoxicity of MRA-CN in these cells.

Animals↗

PubMed1994

The prevalence of oral cancer in relation to the ethnic origin of Israeli Jews.

Smoking, alcohol, and familial background are considered major cofactors in the cause of oral cancer. The purpose of the present study was to determine the relationship between ethnic origin and oral cancer in the Israeli Jewish Population. Data were collected during the years 1970 to 1980 from 342 dental records of patients in Israeli hospitals. Results showed a male/female ratio of 2:1. Of 264 patients with clearly determined ethnic origin, 72% were Ashkenazi, 15% Sephardi, and 13% Eastern ethnic origin. The relative prevalence showed that the risk of the Ashkenazi group to develop oral cancer was at least twice as high as the other two ethnic groups. The increase in occurrence of oral cancer with age in each ethnic group was highly significant (p < 0.001). The most common type of malignancy was squamous cell carcinoma (95%) with 99% of this malignancy occurring in patients in their sixth and seventh decade. A significant (p < 0.02) relationship between site of involvement and ethnic origin was also noted. The tongue was the leading site in the Ashkenazi and Sephardi groups, whereas the lip and alveolar ridges were the most affected sites in the Eastern ethnic group.

Adult↗

PubMed1994

Chlorambucil induced apoptosis in chronic lymphocytic leukemia (CLL) and its relationship to clinical efficacy.

Chlorambucil induced apoptosis was measured in CLL cells treated with clinically achievable drug doses in vitro. While spontaneous apoptosis occurred in CLL cells incubated in vitro in the absence of drug, the level of apoptosis, as measured by the extent of DNA fragmentation, was greater in cells treated with chlorambucil. In addition, macrophages were shown to engulf drug treated CLL cells in vitro. To determine if chlorambucil can also induce apoptosis in vivo, CLL cells were isolated from patients before treatment and at intervals after clinical therapy with chlorambucil (0.9 mg/kg given over 3 days). Apoptosis was measured in these cells immediately after isolation and following incubation in vitro for 72 hr. No apoptotic changes were detected in cells immediately after isolation either before or after clinical treatment. In contrast, apoptosis was observed in cells that were incubated ex vivo for 72 hr, and the level of apoptosis was greater in cells that were isolated after chlorambucil treatment compared with cells obtained prior to therapy. The increased apoptosis observed in CLL cells ex vivo after therapy was related to the fall in the patient's lymphocyte count. In general, a large increase in apoptosis ex vivo after treatment was followed by a significant decrease in the patient's lymphocyte count. Thus, chlorambucil may produce its antitumor effect in CLL by inducing apoptosis-associated membrane changes that result in rapid clearance of the apoptotic cells by the immune system.

Apoptosis↗

PubMed1994

Combination therapy with nucleoside analogs and alkylating agents.

The nucleoside analog, 2'-deoxycoformycin (dCF), and the alkylating agents, chlorambucil (CLB) and cyclophosphamide, are effective agents in the treatment of chronic B cell leukemias and lymphomas. The cyclophosphamide analog, 4-hydroperoxycyclophosphamide (4-HC), generates the same active metabolite as cyclophosphamide in cells and has been used extensively for bone marrow purging in vitro. We have observed that deoxyadenosine (dAdo) plus dCF (dAdo/dCF) inhibit the repair of x-irradiation-induced and bleomycin-induced DNA damage in vitro, and that this results in either synergistic or additive cytotoxicity, respectively. In the present study we examined whether dAdo/dCF, can enhance the antitumor activity of CLB and 4-HC in chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells were treated with CLB for 6 hr and then with dAdo/dCF for 18 hr and cytotoxicity was measured by the MTT assay. Synergy was observed between CLB and dAdo/dCF in CLL cells from 2 patients, with synergy increasing as the CLB dose was raised. In contrast, similar treatment of human bone marrow cells resulted in little or no synergistic cell kill. Treatment of CLL cells from 2 patients with 4-HC for 30 min followed by dAdo/dCF for 18 hr resulted in little synergistic cytotoxicity, although this drug combination did produce an additive cell kill. Thus, combination therapy with nucleoside analogs and alkylating agents may be useful for improving treatment of CLL.

Alkylating Agents↗

PubMed1993

Prevention of insulin-dependent diabetes mellitus by 2'-deoxycoformycin in the BB Wistar rat.

The effect of the adenosine deaminase (ADA) inhibitor 2'-deoxycoformycin (dCF) on the development of insulin-dependent diabetes mellitus (IDDM) was assessed in the BB Wistar rat. Sixty-one male rats were treated from days 30 to 120 with 0, 0.5, 1.0 or 1.5 mg dCF/kg/week. The incidence of IDDM was 78% in the controls and was significantly (P < 0.01) decreased in rats receiving 1.5 mg dCF/kg/week (32%), but not in rats receiving lower doses of the drug. However, for those rats that became diabetic the mean time to the development of IDDM was unchanged in animals receiving dCF compared with control. dCF treatment did not produce significant weight loss in the animals or gross changes in the thymus, spleen or kidneys. Although the protective effect of dCF against IDDM was likely produced by immunosuppression, the different dCF dosages had similar effects on ADA suppression in spleen or thymus and on dATP accumulation in these organs.

Adenosine Deaminase Inhibitors↗

PubMed1993

Role of transforming growth factor-beta in chronic lymphocytic leukemia.

TGF-beta is an important immunoregulator as it suppresses proliferation and function of B- and T-lymphocytes. In the present study we have examined the cellular localization and secretion of TGF-beta in B-cells from normal donors and patients with CLL and have assessed the influence of TGF-beta 1 on DNA synthesis in these cells. Using anti-LC(1-30)--a polyclonal anti-TGF-beta 1 antibody--TGF-beta was localized to discrete sites within the cytoplasm of both normal and malignant lymphocytes. These areas co-localized with areas detected by an antigranule antibody (D545), suggesting that TGF-beta may be stored within cytoplasmic secretory vesicles. Both normal B- and CLL cells contained low or undetectable levels of TGF-beta mRNA and secreted low and equivalent amounts of TGF-beta. Compared to untreated cells, DNA synthesis was reduced by TGF-beta 1 to a mean +/- S. E. of 0.84 +/- 0.07 in CLL cells and this was significantly less (p < 0.001) than that observed in normal B-cells (mean +/- S. E. of control, 0.12 +/- 0.02). In 3 of the 18 patients, TGF-beta 1 stimulated DNA synthesis. The reduced inhibition of leukemic cell DNA synthesis by TGF-beta 1 in CLL may provide these cells with a growth or survival advantage over normal lymphocytes and contribute to their selective accumulation.

DNA, Neoplasm↗

PubMed1993

Role of NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase) in activation of mitomycin C under acidic conditions.

The quinone antitumor agent mitomycin C is preferentially toxic to some cells under hypoxic and acidic conditions. The two-electron reducing enzyme DT-diaphorase may be a major contributor to mitomycin C activation under aerobic conditions, but its role in drug activation under hypoxic and acidic conditions is unclear. In this study, we observed that mitomycin C produced increased DNA cross-linking and cytotoxicity in Chinese hamster ovary cells at pH 6.6, compared with pH 7.2, under aerobic conditions, but drug activity was similar at these pH values under hypoxic conditions. The DT-diaphorase inhibitor dicoumarol completely inhibited the enhanced activity of mitomycin C at acidic pH under aerobic conditions but had no effect on DNA cross-linking or cytotoxicity under hypoxic conditions. These finding suggest that the enhanced activity of mitomycin C at acidic pH, in air, is due to increased drug activation by DT-diaphorase. However, the role of DT-diaphorase in activating mitomycin C under hypoxic conditions appears to be limited, even at acidic pH.

Animals↗

PubMed1992

Inhibition of repair of bleomycin-induced DNA strand breaks by 2'-deoxycoformycin and its effect on antitumor activity in L5178Y lymphoblasts.

We have observed previously that treatment of plateau-phase L5178Y murine lymphoblasts in vitro with 2'-deoxycoformycin plus deoxyadenosine (dCF/dAdo) can inhibit the repair of X-irradiation-induced DNA single-strand breaks (SSB) in these cells and that this effect is associated with synergistic cell kill. In this study we examined the effect of a combination treatment of plateau-phase L5178Y cells with bleomycin (BLM) plus dCF/dAdo. Incubation of BLM-treated cells with dCF/dAdo resulted in significant inhibition of the repair of BLM-induced DNA SSB. However, an additive, but not a synergistic, increase in cell kill was observed when cells were treated with a combination of BLM plus dCF/dAdo.

Animals↗

PubMed1992

Antiproliferative properties of aminosteroid antioxidants on cultured cancer cells.

The antiproliferative properties of three 21-aminosteroid antioxidants (lazaroids), 21-[4-[5,6-bis(diethylamino)-2-pyridinyl]-1- piperazinyl]-16 alpha-methylpregna-1,4,9(11)triene-3,20-dione, hydrochloride (U74500A), 21-[4-(2,6-di-1-pyrrolidinyl-4-pyrimidinyl)-1-piper- azinyl]-pregna-1,4,9(11)-triene-3,20-dione, monomethanesulfonate (U74389F), 2H-1-benzopyran-6-ol, 2-[[4-[3-(ethylamino)-2-pyridinyl]-1-piperzinyl]methyl]-3,4- dihydro-2,5,7,8-tetramethyl-, (Z)-2-buten dioate (U78518F), on human breast cancer cells are described. U74500A inhibited cell proliferation in a dose-dependent manner with IC50 values of approximately 1.7 and 1.2 microM when cells were exposed to the drug for 3 and 5 days, respectively. The non-steroid antioxidants, alpha-tocopherol and nordihydroguaiaretic acid, showed weak or no activity at the same dose range. All three lazaroids inhibited, dose dependently, the proliferation of mouse lymphocytes but only at IC50 values ranging between 20-30 microM. The specificity of action was studied by including other steroids: progesterone, testosterone and hydrocortisone. Both sex hormones stimulated cell proliferation at low (less than 10(-5) M) concentrations but inhibited at higher doses with IC50 values of 26 (progesterone) and 80 (testosterone) microM. Hydrocortisone (IC50 0.17 microM), on the other hand, inhibited cell proliferation by 70% over a wide range of doses. Human breast cancer cells appear to have a greater sensitivity than the mouse lymphocytes to lazaroids. The antiproliferative effects of lazaroids in cancer cells may be, at least in part, due to an interaction with glucocorticoid receptors.

Animals↗

PubMed1992

Factors influencing the inhibition of repair of irradiation-induced DNA damage by 2'-deoxycoformycin and deoxyadenosine.

Permeabilized L5178Y cells were used to investigate the mechanism underlying inhibition of the repair of irradiation-induced DNA strand breaks by 2'-deoxycoformycin combined with deoxyadenosine. Permeabilized cells repaired DNA strand breaks as effectively as did intact cells, and at deoxyadenosine concentrations that produced similar levels of deoxyadenosine triphosphate (dATP), repair of DNA strand breaks was inhibited by 2'-deoxycoformycin plus deoxyadenosine to a comparable extent in both types of cells. Accompanying the increase in intracellular dATP produced by 2'-deoxycoformycin combined with deoxyadenosine was a fall in levels of deoxythymidine triphosphate (dTTP), deoxyguanosine triphosphate (dGTP), and deoxycytidine triphosphate (dCTP). The addition of dTTP, dGTP, and dCTP reversed the inhibition of DNA repair by 2'-deoxycoformycin plus deoxyadenosine, although the level of dATP was not affected. Reducing the phosphorylation of deoxy-adenosine to dATP by the addition of adenosine prevented the decrease in levels of dTTP, dGTP, and dCTP and the inhibition of DNA repair by 2'-deoxycoformycin and deoxyadenosine. In contrast, increasing the intracellular levels of dATP by the addition of 2'-deoxycoformycin together with dATP, deoxyadenosine diphosphate (dADP), or deoxyadenosine monophosphate (dAMP) had no effect on the levels of the other deoxynucleotide triphosphates and did not inhibit DNA repair. Moreover, DNA repair was not inhibited by the breakdown products of deoxyadenosine, adenine, or deoxyribose. These results suggest that inhibition of the repair of irradiation-induced DNA strand breaks by 2'-deoxycoformycin combined with deoxyadenosine requires the phosphorylation of deoxyadenosine and involves alterations in the levels of deoxynucleotide triphosphates.

Adenosine↗

PubMed1992

Induction of apoptosis in CD4+ prolymphocytic leukemia by deoxyadenosine and 2'-deoxycoformycin.

The leukemic cells of a patient with CD4+ prolymphocytic leukemia were treated in vitro with 5 microM deoxyadenosine and 60 microM 2'-deoxycoformycin (dCF), an inhibitor of adenosine deaminase (ADA). Following treatment, the leukemic cell dATP level increased to 378 pmol/10(6) cells on day 3, after which the level plateaued. Apoptosis was apparent following 4 h of incubation, and by day 8 34% of the chromatin was fragmented. Apoptosis also occurred in control cells, but to a lesser extent than in drug-treated cells. When the patient was treated with dCF, 4 mg/M2 i.v. the leukemic cell ADA activity was inhibited 24 h following treatment, and the lymphocyte dATP content increased to 303 pmol/10(6) cells by day 6. The lymphocyte count fell 60% in 1 week, but during this time there was no evidence of apoptosis in these cells. Thus, if dCF induces apoptosis in vivo, the effete cells may be rapidly cleared from the circulation and thus elude detection.

Adenosine Deaminase Inhibitors↗

PubMed1992

Role of NAD(P)H:(quinone acceptor) oxidoreductase (DT-diaphorase) in activation of mitomycin C under hypoxia.

The role of the two-electron reducing enzyme DT-diaphorase in the activation of mitomycin C under hypoxic conditions was investigated. Mitomycin C activity was compared in L5178Y murine lymphoblasts, which have low levels of DT-diaphorase activity, and L5178Y/HBM10 cells, which have elevated levels of enzyme activity. The cytotoxic and DNA cross-linking activities of mitomycin C were greater in L5178Y/HBM10 cells than in L5178Y cells. In L5178Y/HBM10 cells, dicoumarol, an inhibitor of DT-diaphorase, decreased cell kill and DNA cross-linking by mitomycin C in air but had no significant effect on these activities under hypoxia. By comparison, in L5178Y cells, dicoumarol had no effect on drug activity under either aerobic or hypoxic conditions. A model for the activation of mitomycin C by both one-electron and two-electron reduction is proposed. Our findings suggest that two-electron reduction by DT-diaphorase has only a limited role in the activation of mitomycin C under hypoxic conditions, although this enzyme appears to be an important contributor to drug activation under aerobic conditions.

Animals↗

PubMed1992

Role of glutathione and glutathione S-transferase in chlorambucil resistance.

A chlorambucil (CLB)-resistant cell line, N50-4, was developed from the established mouse fibroblast cell line NIH 3T3, by multistep drug selection. The mutant cells exhibited greater than 10-fold resistance to CLB. Alterations in GSH and glutathione S-transferase (GST) were found in CLB-resistant variants. A 7-10-fold increase in cellular GSH content and a 3-fold increase in GST activity were detected in N50-4 cells, compared with parental cells, as determined by enzymatic assays. An increase in steady state levels of the GST-alpha isozyme mRNA was found in the CLB-resistant cells, as analyzed by Northern blotting. No GST gene amplification or rearrangement was shown by Southern blot analysis. To test the relative roles of GSH and GST in CLB resistance, a number of GSH- and GST-blocking agents were used. The CLB toxicity was significantly enhanced in N50-4 cells by administration of either the GSH-depleting agent buthionine sulfoximine or the GST inhibitors ethacrynic acid or indomethacin. The resistance to CLB cytotoxicity in N50-4 cells, however, was still significantly higher than that of parental cells. The resistance of N50-4 cells to CLB was almost completely abolished by combination pretreatment yielding both GSH depletion and GST inhibition. The results indicate that both increased cellular GSH content and increased GST activity play major roles in CLB resistance in N50-4 mutant cells.

3T3 Cells↗

PubMed1991

Mechanisms of resistance to chlorambucil in chronic lymphocytic leukemia.

The postulated biochemical mechanisms responsible for clinical resistance to chlorambucil (CLB) in chronic lymphocytic leukemia (CLL) have been examined. The total sulfhydryl, non-protein-bound sulfhydryl, protein-bound sulfhydryl (PSH) and glutathione (GSH) levels, in addition to glutathione S-transferase (GST) activities, were measured in the leukemic cells of 18 CLL patients. In addition, the formation and repair of DNA cross-links were measured following incubation of the cells with 100 microM chlorambucil in vitro. These parameters were then correlated with the subsequent clinical responses of the patients, as measured by the percent fall in lymphocyte count 3 weeks following 0.9 mg/kg chlorambucil. No correlations were observed between any of the individual parameters and clinical response, although a slight positive correlation was observed between the PSH:GSH ratio and clinical response. These findings suggest that multiple mechanisms may contribute to CLB-resistance in CLL.

Aged↗

PubMed1991

Mechanisms for the modulation of alkylating activity by the quinone group in quinone alkylating agents.

Previous studies have demonstrated that the quinone group may play an important role in modulating the alkylating activity of quinone alkylating agents. Introduction of a quinone moiety markedly increased the alkylating activity and cytotoxic activity of the model quinone alkylating agents benzoquinone mustard and benzoquinone dimustard. However, the cytotoxic and DNA-damaging activity of benzoquinone mustard was considerably greater than that of benzoquinone dimustard. In this study, we have investigated the role of the quinone group as a modulator of alkylating activity in these antitumor agents, using extracellular assays to eliminate differences due to cellular drug uptake and metabolism. Evidence was obtained that the alkylating activities of both benzoquinone mustard and benzoquinone dimustard were enhanced by reduction of the quinone group. In addition, when these agents were reduced, they displayed equal alkylating activity. This finding suggests that the difference in the activity of these agents in cells is not due to intrinsic differences in alkylating activities of the activated forms of these agents. Electrochemical studies revealed that benzoquinone dimustard has a lower redox potential than benzoquinone mustard and, thus, is less easily reduced. Inactivation and spectroscopic studies suggested that a major reason for the differences in activity between benzoquinone mustard and benzoquinone dimustard may be the rapid inactivation of the dimustard before its reduction. This effect may be enhanced by the lower redox potential of benzoquinone dimustard, compared with benzoquinone mustard. These findings support the hypothesis that the quinone group can modulate the alkylating activity of quinone alkylating agents; however, the mechanisms by which this modulation occurs may vary for different antitumor agents.

Alkylating Agents↗

PubMed1990

Activity of quinone alkylating agents in quinone-resistant cells.

The role of the quinone group in the antitumor activity of quinone alkylating agents, such as mitomycin C and 2,5-diaziridinyl-3,5-bis(carboethoxyamino)-1,4-benzoquinone, is still uncertain. The quinone group may contribute to antitumor activity by inducing DNA strand breaks through the formation of free radicals and/or by influencing the alkylating activity of the quinone alkylators. The cytotoxic activity and DNA damage produced by the model quinone alkylating agents, benzoquinone mustard and benzoquinone dimustard, were compared in L5178Y murine lymphoblasts sensitive and resistant to the model quinone antitumor agent, hydrolyzed benzoquinone mustard. The resistant cell lines, L5178Y/HBM2 and L5178Y/HBM10, have increased concentrations of glutathione and elevated catalase, superoxide dismutase, glutathione S-transferase, and DT-diaphorase activity. L5178Y/HBM2 and L5178Y/HBM10 cells were 7.4- and 8.5-fold less sensitive to benzoquinone mustard and 1.7- and 4.3-fold less sensitive to benzoquinone dimustard, respectively, compared with sensitive cells, but showed no resistance to the non-quinone alkylating agent, aniline mustard. The formation of DNA double strand breaks by benzoquinone mustard was reduced by 2- and 8-fold in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, while double strand break formation by benzoquinone dimustard was reduced only in the L5178Y/HBM10 cells. The number of DNA-DNA cross-links produced by benzoquinone mustard was 3- and 6-fold lower, and the number produced by benzoquinone dimustard was 35% and 2-fold lower in L5178Y/HBM2 and L5178Y/HBM10 cells, respectively, compared with L5178Y parental cells. In contrast, cross-linking by aniline mustard was unchanged in sensitive and resistant cells. Dicoumarol, an inhibitor of DT-diaphorase, increased the cytotoxic activity of both benzoquinone mustard and benzoquinone dimustard in L5178Y/HBM10 cells. This study provides evidence that elevated DT-diaphorase activity in the resistant cells contributes to resistance to benzoquinone mustard and benzoquinone dimustard, possibly by decreasing the formation of the semiquinone intermediates of these agents. The altered reduction of the quinone groups in the resistant cells may be responsible for the decreased DNA-DNA cross-linking and lowered induction of DNA strand breaks by the quinone alkylating agents. These findings demonstrate that the quinone group can modulate the activity of quinone alkylating agents. The study also suggests that the semiquinone intermediates of benzoquinone mustard and benzoquinone dimustard may be the active alkylating species of these two agents.

Alkylating Agents↗

PubMed1990

Glutathione S-transferase activity, sulfhydryl group and glutathione levels, and DNA cross-linking activity with chlorambucil in chronic lymphocytic leukemia.

Glutathione (GSH) levels and glutathione S-transferase (GST) activities were measured in the leukemia cells of 12 patients with chronic lymphocytic leukemia. Both were correlated with prior clinical exposure to alkylating agents and with DNA cross-link formation by chlorambucil in these cells in vitro. No correlation was observed between prior exposure to alkylating agents and GSH level or GST activity. An inverse correlation was observed between GST activity and cross-linking by chlorambucil, which was enhanced if both GST activity and GSH level were related to cross-linking. These findings suggest that the combination of GST and GSH protects the DNA of leukemia cells from chlorambucil, but the role of this combination in clinical resistance remains to be determined.

Adult↗