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Biomedical subjects

E L Schwartz

Publications and source records attributed to E L Schwartz.

At least 19 recordsLinked to original sources
PubMed1992

Stimulation of 5-fluorouracil metabolic activation by interferon-alpha in human colon carcinoma cells.

Interferon-alpha (IFN alpha) increases the cytotoxicity of 5-fluorouracil (FUra) in vitro, and the combination has clinical efficacy against advanced colorectal cancer. IFN alpha treatment of HT-29 colon carcinoma cells induced a greater than two-fold increase in the intracellular levels of the active metabolite of FUra, FdUMP. Using cell extracts from HT-29 cells and FUra as substrate, IFN alpha produced a 1.9- and 8.7-fold increase, respectively, in the activities of uridine phosphorylase and pyrimidine nucleoside phosphorylase (PyNP). Furthermore, the effect was selective for the conversion of FUra to FdUMP, as IFN alpha did not increase the cellular levels of FUTP, nor did it change the extent of incorporation of FUra into RNA (or DNA). IFN alpha also had no effect on thymidine kinase activity, the second step in the activation of FUra. Hence the effect of IFN alpha on PyNP activity is likely a critical biochemical event that modulates the cytotoxicity of FUra.

Adenosine↗
PubMed1992

Principles in the biomodulation of cytotoxic drugs by interferons.

The interferons (IFNs) were identified as novel, endogenous antiviral agents in 1957. Shortly thereafter, antiproliferative and immunostimulatory activities were identified for these compounds. Based on these observations, partially purified IFNs entered clinical trials in the 1970s and recombinant IFNs in 1980. IFNs have demonstrated important clinical activity in hairy cell leukemia, melanoma, renal cell carcinoma, and Kaposi's sarcoma as monotherapy. Shortly after their introduction into clinical trials, however, preclinical studies demonstrated synergistic interactions between IFNs and cytotoxic drugs. Numerous preclinical trials have demonstrated a broad spectrum of interactions between IFNs and at least 20 cytotoxic agents both in vitro and in vivo. Early clinical trials suggest a benefit to combinations of fluorouracil and recombinant interferon alfa in refractory gastrointestinal malignancies. Combinations of IFNs and cytotoxic agents deserve further investigations; however, different principles apply for combining IFNs with cytotoxic drugs than for the design of combination chemotherapy regimens.

Antineoplastic Agents↗
PubMed1992

Pharmacokinetic interactions of zidovudine and methadone in intravenous drug-using patients with HIV infection.

Pharmacokinetic parameters for methadone and zidovudine (ZDV), alone and in combination, were determined in 14 HIV-infected individuals including nine former intravenous drug users (IVDU) who were receiving methadone maintenance therapy. The serum levels of methadone were measured prior to and after initiation of ZDV treatment, with each patient serving as his or her own control. Concurrent administration of ZDV did not alter either the peak methadone concentration or the area under the methadone concentration-time curve (AUC). Serum and urine ZDV and ZDV-glucuronide concentrations were measured by both high pressure liquid chromatography (HPLC) and radioimmunoassay (RIA), and pharmacokinetic parameters determined at least twice in each of nine methadone-maintained former IVDU patients initiating ZDV therapy. These parameters were compared to those for ZDV in a group of five control patients who were neither receiving methadone nor had a history of i.v. drug use. The serum ZDV levels were significantly higher in the methadone patients, with a 43% increase (p less than 0.05) over the mean AUC of 7.68 microM h observed in the control patients. Furthermore the methadone patients could be divided into two groups based on their ZDV AUC: four patients whose ZDV AUC averaged twofold higher than the control group, and five patients whose ZDV AUC were equal to control. No significant differences were found between the control and methadone groups for ZDV bioavailability or Tmax, serum half-life, glucuronidation, or urinary excretion. Methadone also did not affect ZDV glucuronidation in an in vitro assay using human hepatic microsomes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Regulation of c-myc expression by granulocyte-macrophage colony-stimulating factor in human leukemia cells.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates both the proliferation and functional properties of normal and leukemic myeloid cells via cell surface receptors. The postreceptor mechanisms for these two actions, and the extent to which they represent overlapping biochemical pathways, have not been fully clarified. We have examined the actions of GM-CSF on the expression of c-myc, an early response oncogene associated with the proliferative stimulus of growth factors. GM-CSF reduced the population doubling time of HL-60 leukemia cells from 32 hours to 25 hours, and, at concentrations that were correlated with mitogenicity, induced a rapid twofold increase in the level of c-myc mRNA. Nuclear runoff studies indicated that GM-CSF approximately doubled the transcription rate of c-myc by reversing the transcription attenuation that occurs at the exon 1-intron 1 junction. GM-CSF had no effect on the half-life of c-myc messenger RNA. The biochemical basis for the modulation of c-myc expression by GM-CSF was explored. GM-CSF treatment caused intracellular alkalinization of the cells as measured using the fluorescent probe 2', 7-bis (2-carboxyethyl)-5(and-6) carboxyfluorescein (BCECF). The sodium channel blocker amiloride prevented the GM-CSF-induced change in pH, but did not affect the stimulation of c-myc transcription by GM-CSF. Agents that increase cellular cyclic adenosine monophosphate (cAMP) levels (prostaglandin E2 and cholera toxin) blocked the actions of GM-CSF on c-myc; however, these agents also reduced the basal level of c-myc expression. GM-CSF caused a rapid (5 minutes) and transient decline in cellular cyclic guanosine monophosphate (cGMP) levels, and a slower (30 minutes) and transient decrease in cellular cAMP levels. These observations are consistent with the hypothesis that the declines in cAMP and cGMP are associated with a stimulation of HL-60 proliferation, while previously reported manipulations that elevate cyclic nucleotides are related to an inhibition of HL-60 proliferation and the potentiation of differentiation.

Amiloride↗
PubMed1990

Inhibition of c-myc expression in human promyelocytic leukemia and colon adenocarcinoma cells by 6-thioguanine.

A rapid decrease in expression of the oncogene c-myc has been associated with the induction of differentiation of HL-60 human leukemia cells. In this manner, the treatment of a hypoxanthine phosphoribosyltransferase (HPRT)-deficient HL-60 variant (HL-60/var) with 6-thioguanine (TG) was accompanied by lower c-myc mRNA levels. This occurred in the absence of 6-thioguanosine 5'-monophosphate (TGMP) synthesis and without alterations in cellular nucleotide pool sizes. Paradoxically, inhibition of c-myc expression in the wild type HL-60 (HL-60/wt) cell, which is only weakly induced to differentiate by TG, was 5-fold more sensitive to the thiopurine (IC50 = 35 microM). Furthermore, inosine, which blocks the formation of TGMP and enhances the extent of differentiation of HL-60/wt cells, decreased the sensitivity of c-myc expression in the HL-60/wt to TG. These actions of TG and inosine on c-myc were also observed in the human colon carcinoma cell line COLO 320, further dissociating some of the effects of TG on c-myc expression from granylocytic differentiation. The hematopoietic granulocyte-macrophage colony stimulating factor (GM-CSF) elevated c-myc expression and antagonized the actions of TG on c-myc in the HL-60 cells. GM-CSF more readily antagonized the inhibitory action of TG in the HL-60/var cell line when compared to the HL-60/wt cells, restoring c-myc levels to that of the untreated controls. Hence, TG inhibited c-myc expression by two distinct mechanisms in cells which express high levels of the oncogene: a TGMP-dependent, differentiation-independent process with an IC50 of 35 microM, and a TGMP-independent action with an IC50 of 175 microM that was associated with induction of differentiation and was reversed more readily by GM-CSF.

Adenocarcinoma↗
PubMed1990

Interaction of fluorouracil and interferon in human colon cancer cell lines: cytotoxic and cytokinetic effects.

Fluorouracil (FUra) is the most active agent in advanced colorectal carcinoma, and this activity can be enhanced by various modulating agents both in vitro and in vivo. To determine whether interferon (IFN) is capable of augmenting the cytotoxic and cytokinetic effects of FUra, combinations of FUra and IFN alpha, -beta, and -gamma were tested against 2 human colon cancer cell lines in vitro. In a clonogenic assay, IFN alpha and -beta, at concentrations that produced less than 1 log cell kill, significantly increased the cytotoxic effects of FUra in both cell lines. IFN gamma also enhanced the cytotoxic effects of FUra, but unlike IFN alpha and -beta, only at the highest concentrations tested. Median effects analysis demonstrated that all 3 IFNs exhibited synergy with FUra. Combinations of IFNs were no more effective at modulating FUra activity than single agent IFN. Flow cytometric studies indicated that these effects did not correlate with cytokinetic alterations. Only the combination of FUra and IFN beta produced cytokinetic effects different from those of FUra alone. Incubation with IFN alpha or IFN gamma for 24 h resulted in only modest cytokinetic alterations, and they did not modify the effects of FUra. These results indicate that IFN is capable of increasing the cytotoxic actions of FUra and that this is separable from any cytokinetic effects produced by the interferons.

Cell Cycle↗
PubMed1990

Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review.

The combination of interferon (IFN) and conventional chemotherapeutic agents offers a promising therapeutic approach for the treatment of cancer. However, there is as yet no consensus on optimal strategies for combining this family of compounds with other cancer therapies. While in vitro studies have demonstrated both direct cytotoxic and cytokinetic effects for IFN, a more interesting role derives from its ability to synergistically potentiate the activity of a wide variety of cytotoxic agents against multiple human and rodent tumors, both in vitro and in animal models. The interaction between IFN and cytotoxic agents in vitro is complex and depends not only on the choice of cytotoxic agent but also on the concentrations, ratios, duration, and sequence of exposure to the two drugs. Preliminary data suggest that some combinations are not merely additive but rather that IFN may biochemically modulate the cellular uptake or metabolism of the cytotoxic agent resulting in synergistic antineoplastic activity. In vivo interactions between IFN and cytotoxic agents involve an additional layer of complexity because of the potential effects of the biological agent on the host immune system and drug-metabolizing enzymes. Furthermore, IFN may have a protective effect on normal host tissues which theoretically could allow for the delivery of higher doses of cytotoxic agents. The results of early clinical trials using combinations of IFN with chemotherapeutic agents have generally been disappointing. This may be due to the inability of preclinical models to accurately predict the clinical situation or alternatively from a failure to incorporate information on dose, scheduling, and sequence of drug administration into clinical trials. Preliminary clinical studies with IFN-alpha and the fluorinated pyrimidine, 5-fluorouracil, in patients with advanced colorectal carcinoma suggest that IFN may enhance the effects of the antimetabolite. Confirmatory trials are in progress. Further trials designed to exploit the preclinical experience with combinations of IFN and cytotoxic agents are warranted.

Animals↗
PubMed1990

Cat and monkey cortical columnar patterns modeled by bandpass-filtered 2D white noise.

A simple algorithm based on bandpass-filtering of white noise images provides good quality computer reconstruction of the cat and monkey ocular dominance and orientation column patterns. A small number of parameters control the frequency, orientation, "branchedness", and "regularity" of the column patterns. An oriented (anisotropic) bandpass filter followed by a threshold operation models the macaque ocular dominance column pattern and cat orientation column system. An unoriented (isotropic) bandpass filter models the cat ocular dominance column pattern and the macaque orientation column system. The resemblance of computer graphic simulations produced by this algorithm and histological pattern data, is strong. Since this algorithm is very fast, we have been able to extensively explore its parameters space in order to determine filter parameters which closely match the structure of the various cortical systems. In particular, we have applied spectral analysis to our recent computer reconstruction of the macaque ocular dominance column system, and the model produced by the present algorithm is in close agreement with this detailed data analysis.

Algorithms↗
PubMed1990

Phase II trial of etoposide, doxorubicin (Adriamycin), and cisplatin (EAP regimen) in advanced gastric cancer.

Ten previously untreated patients with gastric cancer were treated with etoposide, 120 mg/m2 intravenously (i.v.) on days 4, 5, and 6, Adriamycin, 20 mg/m2 i.v. on days 1 and 7, and cisplatin, 40 mg/m2 i.v. on days 2 and 8 (EAP). Etoposide, 240 mg/m2 on days 4, 5, and 6, was administered orally instead of intravenously in alternating cycles, and pharmacokinetic studies were performed in those who had previously undergone gastrectomy or who had tumor infiltrating the stomach to determine oral bioavailability. Nine patients had advanced measurable gastric cancer, and one patient had an elevated carcinoembryonic antigen after surgery for synchronous gastric and colon cancer. The median age was 54 years (range 38-69), and the median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0-3). Nine of 10 patients had poorly differentiated adenocarcinoma. Twenty-four cycles were administered to 10 patients, and hematologic data were available for 23 courses. ECOG grade 4 neutropenia and thrombocytopenia developed in 19 (83%) and 8 (53%) courses, respectively. Thirteen courses (54%) were complicated by fever requiring parenteral antibiotics. Two patients (20%) died due to neutropenic sepsis. The profound myelotoxicity observed in our study prompted us to terminate the investigation prior to completing accrual. The oral bioavailability of etoposide was 21% and 36% in the two patients who had had prior gastrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma↗
PubMed1989

Activation of 2',5'-oligoadenylate synthetase activity on induction of HL-60 leukemia cell differentiation.

A 27-fold increase in 2',5'-oligoadenylate synthetase activity, an enzyme associated with the antiproliferative actions of interferon (IFN), was observed after treatment of HL-60 human leukemia cells with dimethyl sulfoxide (DMSO), an inducer of granulocytic differentiation of the cells. Enzyme activity was elevated after 24 h of exposure to DMSO, was maximal at 48 hours, and declined thereafter. A comparable increase was observed after treatment with 1 U of alpha interferon (IFN-alpha) per ml or 8 U of beta interferon (IFN-beta) per ml. Elevated levels of expression of other IFN-inducible genes, including type I histocompatibility antigen (HLA-B) mRNA and 2',5'-oligoadenylate phosphodiesterase activity, were also observed with DMSO treatment. DMSO-treated HL-60 cells had an increased amount of a 1.8-kilobase mRNA for oligoadenylate [oligo(A)] synthetase when compared with that of control cells; both DMSO- and IFN-treated HL-60 cells also expressed 1.6-, 3.4-, and 4.3-kilobase mRNA. The increase in both oligo(A) synthetase activity and mRNA levels was inhibited by polyclonal antiserum to human IFN-alpha; however, no IFN-alpha mRNA could be detected in the cells. Antiserum to IFN-beta or gamma interferon (IFN-gamma) had no effect on oligo(A) synthetase expression or activity nor was there any detectable IFN-beta 1 or IFN-beta 2 mRNA in the cells. The anti-IFN-alpha serum did not block the elevation of HLA-B mRNA in DMSO-treated cells. These observations suggest that the increased expression of oligo(A) synthetase in DMSO-treated cells may be mediated by the release of an IFN-alpha-like factor; however, the levels of any IFN-alpha mRNA produced in the cells were extremely low.

2',5'-Oligoadenylate Synthetase↗
PubMed1989

Fluorouracil and recombinant alfa-2a-interferon: an active regimen against advanced colorectal carcinoma.

Based on in vitro studies that have demonstrated synergy between recombinant alfa-2a-interferon (rIFN alpha-2a) and the fluoropyrimidine, fluorouracil (5FU), against two human colon cancer cell lines, a pilot clinical trial was initiated to determine the effects of the combination of 5FU and rIFN alpha-2a in patients with advanced, unresectable colorectal carcinoma. A total of 30 patients were enrolled; all were evaluable. 5FU was administered as a loading course, 750 mg/m2 daily for 5 days by continuous infusion followed by weekly bolus therapy, rIFN alpha-2a, 9 MU, was administered subcutaneously three times per week. Of 17 previously untreated patients evaluable for response, 13 achieved a response. Three patients had disease progression. No previously treated patients had a major response. There was one death clearly related to therapy, an event preceded by watery diarrhea and neutropenic sepsis. Other toxicities were reversible and responded to dose reduction. With a median follow-up of 16+ months, median survival has not been reached among the previously untreated patient cohort. We conclude that the combination of 5FU and rIFN alpha-2a is an active regimen against disseminated colorectal cancer in previously untreated patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Variable regulation of sensitivity to retinoic acid-induced differentiation in wild-type and retinoic acid-resistant HL-60 cells.

The initial cell association and metabolic conversion of retinoic acid (RA) by HL-60 cells in serum-free, transferrin/insulin-supplemented, RPMI 1640 medium was greater than or equal to 10-fold greater than in RPMI 1640 medium containing 10% fetal bovine serum (FBS). This was paralleled under the serum-free conditions by 10-fold greater sensitivity to RA-induced differentiation, which was partially reversed by the addition of purified bovine serum albumin to the same concentration present in 10% FBS. In serum-free HL-1 medium, HL-60 cell sensitivity to RA-induced differentiation was approximately 250-fold less than in serum-free RPMI 1640 medium but, in this comparison, there was little difference in RA cell association or metabolism. A greater than 200-fold RA-resistant HL-60 subline had RA cell-association and metabolism rates similar to those of wild-type cells under all culture conditions. No significant qualitative differences in the high performance liquid chromatography elution patterns of polar metabolites were observed under any circumstances. These results indicate that inherent cellular properties, not associated with gross differences in RA uptake or metabolism, primarily determined the relative sensitivity or insensitivity of HL-60 cells to RA-induced differentiation but that RA responsiveness was markedly regulated by extracellular factors, one of which, serum albumin, appeared to act by decreasing the initial cell association and metabolism of RA, whereas other, as yet unidentified exogenous factors, may have acted independently of these functions.

Cell Differentiation↗
PubMed1989

Nail changes in glandular disease.

There are a number of glandular disorders that can affect the nails. A listing of the diseases and their corresponding nail changes is shown in Table 2. It is imperative to be able to discern this possible etiology from others, such as trauma and shoegear. A good clue to systemic abnormalities affecting the nails is multiple nail involvement. When a glandular disorder is the source of nail pathology, the signs are very often nonspecific. Many pathologies produce similar nail changes, and singular nail changes may be caused by different pathologies. One must use extreme caution in trying to diagnose systemic pathologies from changes observed in nails.

Endocrine System Diseases↗
PubMed1988

Enhanced mitogenic responsiveness to granulocyte-macrophage colony-stimulating factor in HL-60 promyelocytic leukemia cells upon induction of differentiation.

Treatment of HL-60 leukemia cells with the inducers of differentiation dimethyl sulfoxide (DMSO) and 6-thioguanine (TG) reduces the proliferative capacity of the cells. DMSO acted in a serum-independent manner and reversibly inhibited competence to enter S phase after 24 h of treatment. Purified human granulocyte-macrophage colony-stimulating factor (GM-CSF) but not human CSF-1, restored S phase competence and growth of DMSO-treated cells over a 7-day period. GM-CSF had no effect on the saturation density of control cells, even under conditions of reduced growth. Furthermore, GM-CSF antagonized the growth inhibitory actions of TG associated with cytodifferentiation but not those associated solely with TG cytotoxicity. The number of high affinity, cell surface GM-CSF receptors doubled after treatment of HL-60 cells with DMSO for 24 h and reached a maximum 4- to 5-fold increase within 72 h of exposure. The Kd of GM-CSF binding, 240 pM, was comparable to the concentration required to elicit a mitogenic response in DMSO-treated cells. An HL-60 variant that had been selected for resistance to TG-induced growth inhibition and differentiation (R. E. Gallagher et al., Cancer Res., 44: 2642-2653, 1984) was found to have less than 20% of the cell surface GM-CSF receptors when compared to either wild type cells, or a variant line selected for resistance to TG cytotoxicity. These studies demonstrate that HL-60 cells undergoing differentiation simultaneously lose autonomous growth properties and acquire cell surface growth factor receptors and mitogenic responsiveness.

Blood Physiological Phenomena↗
PubMed1987

Phase I clinical and pharmacokinetic study of taxol.

Taxol, selected for clinical trial because of its animal antitumor activity and unique structure and mechanism of action, was administered in Cremophor by i.v. infusion over 6 h in a phase I study. Eastern Cooperative Oncology Group toxicity grading was used. Eighty-three taxol courses were administered to 34 patients. Grade 3-4 hypersensitivity reactions occurred in 4 of 13 courses at the first 2 dose levels, but premedication with dexamethasone, diphenhydramine, and cimetidine resulted in only 3 additional Grade 2 reactions in the next 70 courses. Neurotoxicity, which resolved or improved after stopping therapy, was Grade 1 with 2 of 10 courses of 230 mg/m2 and Grades 1-3 after 11 of 12 courses of 275 mg/m2. Leukopenia, first seen (Grade 1) after 1 of 8 75 mg/m2 courses, was Grades 3-4 after 10 of 34 courses of 175-230 mg/m2 and 10 of 12 courses of 275 mg/m2. The WBC nadir occurred at a median of 10 days and the median time required for normalization of the WBC was 18 days. Alopecia began 2-3 weeks posttaxol in 2 of 9 patients treated with 75-135 mg/m2 and in all 16 patients (Grade 3) treated with 175-275 mg/m2. Grades 1-2 nausea and vomiting occurred in about one-third of the patients treated at a dose of 105 mg/m2 or more. Taxol disappearance from plasma was biphasic; half-lives of the first and second phases after a 275 mg/m2 dose were 0.32 and 8.6 h, respectively. The apparent volume of distribution was 55 liters/m2, and the peak plasma concentration with a dose of 275 mg/m2, which occurred immediately postinfusion, was approximately 8 microM. Only 5% of parent drug was excreted in the urine within 24 h. Minor objective responses were noted in one patient with gastric cancer and another with ovarian carcinoma. In addition, one patient with massive ascites due to metastatic adenocarcinoma from an unknown primary had only minimal sonographic evidence of ascites for 6 months posttreatment. Neurotoxicity and leukopenia were dose limiting in this schedule. The recommended phase II trial dose is 250 mg/m2, with premedication.

Adenocarcinoma↗
PubMed1987

Phase I trial of taxol given as a 24-hour infusion every 21 days: responses observed in metastatic melanoma.

Taxol, a plant product, has significant activity against certain rodent and human xenograft tumors. It promotes microtubule assembly in vitro, in contrast to vinca alkaloids, which inhibit assembly. In this phase I study, taxol was administered as a 24-hour continuous intravenous (IV) infusion in 65 courses to 26 patients. A premedication regimen of dexamethasone, cimetidine, and diphenhydramine was used to prevent the acute hypersensitivity reactions observed in previous studies of taxol. Only one episode of mild stridor occurred in this study. Peripheral neuropathy was the dose-limiting toxicity and was observed in 40% of patients treated at a dose of 250 mg/m2. Significant neutropenia of brief duration was also common. Pharmacokinetic studies by a high-performance liquid chromatography (HPLC) method demonstrated that drug plasma concentrations increased during the 24-hour infusion and then declined rapidly. Peak plasma concentrations correlated with dose, and less than 5% of taxol was excreted in the urine. Most of the drug was bound to serum components. Partial responses of more than 3 months' duration were observed in four of 12 melanoma patients treated. The recommended phase II dose of taxol on this schedule is 250 mg/m2. Priority should be given to the study of taxol in melanoma.

Alkaloids↗
PubMed1979

Quantitative and qualitative aspects of the binding of N-hydroxy-2-acetylaminofluorene to hepatic chromatin fractions.

The binding of a chemical carcinogen to components of hepatic chromatin in male rats was examined. After a single injection of N-[3H]hydroxy-2-acetylaminofluorene ([3H]OH-AAF) covalent binding to chromatin RNA, protein, and DNA occurs. The amount of carcinogen bound to RNA was approximately 5 times greater than to DNA, and 10 times that of the protein. However, loss of carcinogen from RNA with time was rapid, whereas a persistent binding to DNA equal to 15% of the initial values was observed. To localize the initial and persistent DNA-bound carcinogen, the genome was fractionated using two different chromatin fractionation procedures. The procedures used yielded 3 chromatin fractions based on physical characteristics, degree of association with nascent RNA and in vitro template capacity. Based on those parameters, these chromatin fractions have been tentatively classified as template expressed euchromatin, a repressed heterochromatin, and a highly condensed pelleted heterochromatin. With both the glycerol gradient chromatin fractionation procedure and the selective MgCl2 chromatin precipitation procedure, the initial (2 h) binding of carcinogen was greatest on the euchromatin DNA. Loss of carcinogen from the DNA, however, was also significantly faster from the euchromatin when compared to the heterochromatin and the pelleted heterochromatin. By 10 days after a single injection of the carcinogen, the largest amount of bound fluorene residues was located on the pelleted heterochromatin DNA, an apparently repressed portion of the genome, while less than 5% of the initial values were found on either the eu- or heterochromatin. When the rats were fed a 2-acetylaminofluorene-containing diet, loss of carcinogen from the pelleted heterochromatin DNA was enhanced, while loss from the euchromatin DNA was reduced. The covalent nature of the carcinogen modification of DNA was confirmed by thin-layer chromatography (TLC). These studies also demonstrated 2 separate carcinogen-purine base adducts which were identified as N-(guanin-8-yl)-N-AF and 3-(guanin-N2-yl)-N-AAF based on either co-chromatography with an authentic standard or on published Rf-values, respectively. The pelleted heterochromatin DNA had a significantly greater proportion of the 3-guanine-N2 adduct when compared to DNA from either the eu- or heterochromatin.

2-Acetylaminofluorene↗