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R Henschler

Publications and source records attributed to R Henschler.

At least 37 records · Page 2Linked to original sources
PubMed1998

New developments in hematopoietic stem cell expansion.

The possibility of maintaining, manipulating, and expanding human hematopoietic stem cells in ex vivo culture could help to provide patients with autologous and allogeneic stem cell transplants improved in purity and performance and could offer access to gene therapy of the hematopoietic system. Recent advances in the ex vivo culture of immature human hematopoietic progenitor cells and human hematopoietic stem cells have led to experimental evidence for the qualitative and quantitative maintenance and possible numerical expansion of hematopoietic stem cells in ex vivo culture, making ex vivo graft engineering a realistic possibility. This review summarizes recent developments in the field, their regulatory implications and their application in hematopoietic gene therapy.

Animals↗
PubMed1997

Adhesion and migration are differentially regulated in hematopoietic progenitor cells by cytokines and extracellular matrix.

The conditions that control the migratory status of hematopoietic progenitor cells on extracellular matrix (ECM) and that decide whether a cell migrates or adheres are incompletely understood. We analyzed the migratory behavior of murine hematopoietic progenitor cells factor-dependent-cell-paterson (FDCP)-mix and purified lin-Sca1+ bone marrow cells on ECM. We found that migration on fibronectin (Fn) or laminin (Lam) becomes dependent on beta1-integrins if a surface restraint force is introduced by tilting the ECM-coated culture vessels. Under these conditions, migration specifically occured on Fn and Lam, and was not detected on collagen IV-, hyaluronate-, or bovine serum albumin- coated surfaces. Migration depended on the continuous presence of hematopoietic cytokines interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), or stem cell factor (SCF), whereas other cytokines, such as IL-8, macrophage inflammatory protein-1alpha, macrophage-chemotactic and activating factor, and erythropoietin resulted in very little or no migratory response. IL-3 induced migration was synergistically enhanced by other CSFs, but was completely inhibited by addition of transforming growth factor-beta1. In contrast to firm local adhesion of previously cytokine depleted progenitors that was rapidly inducible within 1 hour after exposure to cytokines, preincubation on Fn matrix for 4 to 6 hours was required before cytokines could induce migration. A sudden increase of cytokine concentration reversibly inhibited migration and induced a fully adhesive state; this effect could be prolonged by consecutive stimulation with heterologous cytokines. Whereas cytokines activated resting progenitor cells to migrate on ECM, cell migration speed was regulated by Fn concentration. These results indicate that beta1-integrin-mediated progenitor cell adhesion and migration are differentially regulated by external stimuli and suggest that this regulation corresponds to different activation states of beta1-integrins in hematopoietic progenitor cells.

Animals↗
PubMed1997

Blood progenitor cell (BPC) mobilization studied in multiple myeloma, solid tumor and non-Hodgkin's lymphoma patients after combination chemotherapy and G-CSF.

For blood progenitor cell (BPC) mobilization, standard-dose VIP chemotherapy consisting of etoposide, ifosfamide and cisplatin has previously shown effective tumor reduction in solid tumor patients and sufficient progenitor cell mobilization for autologous blood cell transplantation. Mobilization chemotherapy regimens in multiple myeloma (MM) predominantly consist of melphalan or cyclophosphamide that induce marked cytopenia and considerable variability of progenitor cell collection. We studied whether in MM (n = 13), BPCs were efficiently and reproducibly mobilized with etoposide (500 mg/m2) and ifosfamide (1500 mg/m2), followed by daily s.c. G-CSF (5 micrograms/kg). In parallel, patients with solid tumors or non-Hodgkin's lymphomas (n = 28) treated with etoposide (500 mg/m2), ifosfamide (1500 mg/m2) and cisplatin (150 mg/m2) and identical dosing of G-CSF were analyzed. Before chemotherapy (day 0), on day 7 after chemotherapy and on days of leukapheresis (day 9-14), leukocyte numbers, mononuclear cells (MNCs), CD34+ cells and coexpression of lineage markers were analyzed. Median blood leukocyte numbers were 28,100/microliters (range, 19,600-40,400) on day 10 in myeloma patients and progressively declined over the next 4 days. In contrast, in solid tumor and lymphoma patients leukocyte numbers constantly increased from a median of 12,400/microliters (range, 6000-22,000) to 30,000/microliters (range, 16,300-63,300) between day 10 and day 13 after chemotherapy. Similar to leukocyte counts, median MNC numbers decreased in myeloma patients with successive leukaphereses, but steadily increased in solid tumor and lymphoma patients over the same period. CD34+ cell numbers in the blood peaked between day 9 and 11 (median: 40/microliters) in myeloma patients and then declined. In the solid tumor and lymphoma group, median CD34+ counts in the blood peaked on day 12 after mobilization chemotherapy (median: 100/microliters). The median CD34+ yield per leukapheresis in the myeloma group was 2.2 x 10(6)/kg (range, 1.5-4.7) on day 10, and fell steadily to 0.95 x 10(6)/kg on day 12, whereas in solid tumor/NHL patients median CD34+ cell yields remained between 3.5 and 3.7 x 10(6)/kg from day 10 to day 12 after mobilization chemotherapy (P < 0.001). To obtain sufficient cell numbers for engraftment a median of 2 (range, 1-3) mobilization chemotherapy cycles were needed in MM compared to 1 (range, 1-10) in solid tumor or lymphoma patients, with a median of 5 (range, 2-8) leukaphereses in MM compared to 1 (range, 1-10) (P < 0.05). Taken together, we found that for patients with MM, VP16 and ifosfamide efficiently and predictably mobilizes progenitor cells into the PB with > or = 3 x 10(6)/kg CD34+ cells collected after one to two mobilization chemotherapy cycles.

Adult↗
PubMed1997

The human lysozyme gene undergoes stepwise demethylation during phagocyte maturation.

The lysozyme (LZM) gene provides a very useful model for studies of phagocyte maturation, because its protein synthesis is increased during myelopoiesis and thus most abundant in terminally differentiated and activated phagoyctes. LZM gene expression and DNA methylation were examined in various normal and transformed hematopoietic cells. Two shifts toward LZM gene demethylation coincided with upregulation of expression: activation of expression in myeloid precursor cells was associated with significant demethylation at a CpG dinucleotide within an Alu repeat in the 5' flanking region; high-level expression in different types of mature phagocytic cells was associated with complete demethylation at two additional, intragenic CpG sites contained in Alu sequences. The possibility that methylation changes occurring within the 5' region of the human lysozyme gene could be involved in the transcription of this gene is discussed, as well as a possible role for demethylation in the maintenance of distinct maturation stages during phagocyte development.

Cell Differentiation↗
PubMed1997

Transforming growth factor-beta 1 delays formation of granulocyte-macrophage colony-forming cells, but spares more primitive progenitors during ex vivo expansion of CD34+ haemopoietic progenitor cells.

Ex vivo culture and expansion of autologous haemopoietic transplants has been developed to improve tumour cell purging and accelerate haemopoietic reconstitution by transplantation of increased progenitor cell numbers. We studied the effect of the negative haemopoietic regulator, transforming growth factor beta-1 (TGF-beta 1) on primitive precursors during ex vivo expansion of CD34+ cells. When added directly to methylcellulose colony-forming assays, TGF-beta 1 potently suppressed the development of granulocyte-macrophage colonies from CD34+ enriched peripheral blood progenitor cells (80-90% inhibition). In contrast, expansion of total nucleated cells and granulocyte-macrophage colony-forming cells (GM-CFC) from CD34+ progenitors in liquid culture in the presence of stem cell factor (SCF), interleukin (IL)-1 beta, IL-3, IL-6 and erythropoietin (EPO) was inhibited to 32-65% of control culture levels within 14 d when TGF-beta 1 was added, and still produced an average 3.3-fold absolute amplification of GM-CFC. The inhibitory effect of TGF-beta 1 on GM-CFC generation was reversed when it was washed out on day 6 of ex vivo expansion cultures, and total numbers of GM-CFC generated from expansion cultures then reached levels of untreated controls by day 16. Long-term bone marrow culture-initiating cell (LTCIC) numbers were preserved, at least at input levels, over a culture period of 14 d both in control and TGF-beta-1-treated expansion cultures. These findings suggest that TGF-beta 1, a cytokine which induces apoptosis or terminal differentiation in a number of malignant cell types, may be added to ex vivo expansion cultures without loss of primitive cells from autologous haemopoietic transplants.

Apoptosis↗
PubMed1997

Cytokine and chemokine production by CD34+ haemopoietic progenitor cells: detection in single cells.

In vitro expansion of haemopoietic progenitor cells (HPC), lineage-specific differentiation, and gene transfer are all based on in vitro culture systems using haemopoietic growth factors (HGF). A close control of the actual culture conditions, however, is difficult due to secondary mediators secreted by the heterogenous population of mature and immature cells in culture. Although monocytes and granulocytes have already been identified as active producers, this study specifically addressed the role of CD34+ progenitor cells in this respect. Using an immunostaining method that enables simultaneous detection of cytokines and phenotype, 56 +/- 6% CD34+ peripheral blood progenitor cells (PBPC) were found to contain cytoplasmic IL-8 after stimulation with phorbol myristate acetate + ionomycin for 90 min. 19 +/- 40%, stained positive after TNF-alpha induction (20 h), and 7 +/- 1% expressed IL-8 in the presence of culture medium alone. Intra-cytoplasmic TNF-alpha and IL-1beta were detected at lower frequency, and < 1% of CD34+ cells expressed IL-1ra or IL-6, whereas IL-1alpha, IL-10 and G-CSF were not detected. Thus, CD34+ HPC are able to synthesize chemo- and cytokines that may operate in an auto- or paracrine manner to modulate in vivo as well as in vitro growth and differentation of haemopoietic cells.

Antigens, CD34↗
PubMed1996

Interleukin-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells.

Bcl-2 expression has been shown in hematopoietic progenitor cells. Through the use of Bcl-2 specific antisense oligonucleotides we herein report the biologic importance of Bcl-2 expression in primary human CD34+ hematopoietic progenitor cells committed to the myeloid lineage. In bone marrow or peripheral blood derived CD34+ cells Bcl-2 specific antisense decreased cell survival and inhibited the outgrowth of mixed myeloid colonies. A short-term overnight pretreatment of CD34+ cells with 25 mumol/L of Bcl-2 antisense in liquid culture completely ablated the growth of granulocyte-macrophage colony-forming cells (GM-CFC) in a subsequent 14 days methylcellulose colony assay. Control experiments using corresponding Bcl-2 sense or nonsense oligonucleotides did not significantly impair cell survival or growth of GM-colony-forming unit. Western blot analyses revealed the Bcl-2 antisense dependent inhibition of expression of the Bcl-2 protein in CD34+ progenitor cells. Furthermore, regulation of Bcl-2 expression by various cytokines including interleukin-10 (IL-10) was studied. IL-10's effects on the formation of mixed myeloid colonies were examined in the absence or presence of Bcl-2 specific antisense. In the absence of Bcl-2 antisense IL-10 significantly extended the colony forming potential of mixed myeloid colonies to 14 days. In the presence of Bcl-2 antisense rhIL-10 completely restored GM-CSF driven colony growth. Fluorescent microscopy, Western blot analysis, and reverse transcriptase-polymerase chain reaction revealed the IL-10 dependent increase in cellular expression of Bcl-2 protein and Bcl-2 mRNA transcripts in CD34+ cells. Thus these results show that Bcl-2 expression is necessary for the formation of GM-CSF-dependent colony growth in vitro and that rhIL-10 increases Bcl-2 expression and survival in primary human CD34+ hematopoietic progenitor cells that are committed to the myeloid lineage.

Antigens, CD34↗
PubMed1996

Umbilical cord blood: an alternative to the transplantation of bone marrow stem cells.

Recent in vitro analyses of human UCB have demonstrated the potential of UCB as a source for haematopoietic stem and progenitor cell harvest. Clinical data have further indicated that UCB can be given in vivo to fully and partially HLA-matched siblings or non-familial recipients for marrow reconstitution in genetic disorders as well as malignancies. In comparison to adult peripheral blood, UCB displayed decreased immune responses to alloantigens and was enriched in the numbers of CD34+ progenitor cells with high proliferative and long-term marrow reconstituting potential. Cord blood banks now store large transplantable resources of UCB that are analysed with respect to immunological parameters. Cryopreserved UCB cells may fill the gap in finding a stem-cell transplant for patients who lack a matched related or unrelated donor when a bone marrow transplant is needed.

Blood Preservation↗
PubMed1996

Hematopoietic cell proliferation and differentiation.

The use of colony-stimulating factors to stimulate hematopoietic cell proliferation and differentiation in vivo is under still increasing investigation, particularly in the field of stem cell transplantation. This review discusses recently published results and tries to extrapolate lines of future development from the achievements reached to date.

Animals↗
PubMed1996

Hydroquinone stimulates granulocyte-macrophage progenitor cells in vitro and in vivo.

To investigate whether hydroxylated metabolites of benzene may be responsible for the amplification of granulocyte-macrophage progenitor cells (GM-CFC) observed in mice that inhale benzene, groups of six C57BL6 mice were injected with hydroquinone (HQ) (75 mg/kg) or HQ (50 mg/kg) plus phenol (PHE) (50 mg/kg) twice daily for 11 days. Deviations in blood leukocyte and erythrocyte levels by up to one-third were noted in the treated groups; however, the peripheral blood differential counts were unchanged. Although no changes in bone marrow cellularity were observed in mice treated with HQ, cellularity was decreased by a factor of two in the mice that had received HQ plus PHE. The number of GM-CFC per femur was doubled in both treated groups. In vitro experiments using the murine multipotent hematopoietic progenitor cells FDCP mix also showed a duplication of GM-CFC formation in the presence of HQ at concentrations between 10(-6) M and 10(-10) M. When HQ and PHE were present at equimolar concentrations, significantly increased colony formation was still observed with 10(-12) M of metabolites. The effect was independent of the concentration of GM-colony-stimulating factor used. We suggest that HQ is a major mediator of the stimulatory effect of benzene on GM-CFC in mice. In addition, the in vitro data indicate that a direct effect of GM-CFC is involved.

Animals↗
PubMed1996

Biological and clinical advances in stem cell expansion.

One of the most exciting areas of hematological research is the ex vivo expansion of peripheral blood progenitor cells (PBPC). Several groups clearly demonstrated that the ex vivo expansion of hematopoietic progenitor cells is possible in the presence of various cytokine combination and/or different feeder layer models. This minireview summarizes recent developments in ex vivo expansion systems as well as first clinical applications.

Antigens, CD34↗
PubMed1995

Hematopoietic cell proliferation and hematopoietic growth factors.

In vivo studies using hematopoietic growth factors in humans have more clearly defined the ability of these molecules to accelerate hematopoietic cell proliferation in postchemotherapy aplasia and constitutive marrow deficiency states. Studies applying combinations of two growth factors have been added. Investigation of negative regulators of hematopoietic cell proliferation has opened new approaches to protect against damage or loss of candidate stem cells in vitro or in vivo, as well as to selectively recruit malignant cell populations into cell cycle while protecting benign cells. New insights into the synergism of positive regulators of hematopoietic cell proliferation have come from a panoply of in vitro studies, underscoring the value of growth factors previously not associated with effects on hematopoietic cells that have now been found to confer significant synergism with known hematopoietic regulators.

Animals↗
PubMed1994

Direct comparison by limiting dilution analysis of long-term culture-initiating cells in human bone marrow, umbilical cord blood, and blood stem cells.

Limiting-dilution analysis of long-term culture-initiating cells (LTCIC) is a quantitative method of estimating hematopoietic stem cell activity in clinical samples. We compared the numbers of LTCIC in bone marrow (BM), umbilical cord blood, and blood progenitor cells (obtained from patients with solid tumors at leukapheresis after mobilization with induction chemotherapy and filgrastim administration), using a two-stage long-term culture system and a limiting-dilution technique, scoring cobblestone areas of greater than 15 hematopoietic cells weekly for up to 8 weeks. Samples were obtained from 30 normal BMs, 20 human umbilical cords, and 32 leukapheresis products. Direct comparison of LTCIC in the three sources showed that the median proportions of cells generating hematopoietic foci from unfractionated mononuclear cells at 5 and 8 weeks, respectively, were 1:13,314 and 1:33,949 for BM, 1:12,506 and 1:34,546 for umbilical cord blood, and 1:10,302 and 1:12,891 for leukapheresis product. The estimated proportions of LTCIC from unfractionated mononuclear cells and CD34+ cells were similar in experiments with leukapheresis product. Leukapheresis product was superior to umbilical cord blood and cord blood to BM at 5 and 8 weeks of culture (P = .01). In two-stage long-term cultures, more colonies per flask and CD34+ cells were found in assays of leukapheresis product than in BM or umbilical cord blood cultures (P = .0005). Results obtained by this simplified limiting-dilution analysis correlated well with standard long-term cultures and can be used as a measure of the stem cell population. These data suggest that the incidence of putative stem cells in leukapheresis product and umbilical cord blood are at least comparable with that of BM.

Antigens, CD↗
PubMed1994

Maintenance of transplantation potential in ex vivo expanded CD34(+)-selected human peripheral blood progenitor cells.

CD34(+)-selected hematopoietic progenitor cells are being increasingly used for autotransplantation, and recent evidence indicates that these cells can be expanded ex vivo. Of 15 patients with solid tumors undergoing a phase I/II clinical trial using CD34(+)-selected peripheral blood progenitor cells (PBPCs) after high-dose chemotherapy, we analyzed the frequency of long-term culture-initiating cells (LTCIC) as a measure of transplantation potential before and after ex vivo expansion of CD34+ cells. PBPCs were mobilized by combination chemotherapy and granulocyte colony-stimulating factor (G-CSF). The original unseparated leukapheresis preparations, the CD34(+)-enriched transplants, as well as nonabsorbed fractions eluting from the CD34 immunoaffinity columns (Ceprate; CellPro, Bothell, WA) were monitored for their capacity to repopulate irradiated allogeneic stroma in human long-term bone marrow cultures. We found preservation of more than three quarters of fully functional LTCIC in the CD34(+)-selected fractions. Quantitation of LTCIC by limiting dilution analysis showed a 53-fold enrichment of LTCIC from 1/9,075 in the unseparated cells to an incidence of 1/169 in the CD34+ fractions. Thus, in a single apheresis, it was possible to harvest a median of 1.65 x 10(4) LTCIC per kg body weight (range, 0.71 to 3.72). In addition, in six patients, large-scale ex vivo expansions were performed using a five-factor cytokine combination consisting of stem cell factor (SCF), interleukin-1 (IL-1), IL-3, IL-6, and erythropoietin (EPO), previously shown to expand committed progenitor cells. LTCIC were preserved, but not expanded during the culture period. Optimization of ex vivo expansion growth factor requirements using limiting dilution assays for LTCIC estimation indicated that the five-factor combination using SCF, IL-1, IL-3, IL-6, and EPO together with autologous plasma was the most reliable combination securing both high progenitor yield and, at the same time, optimal preservation of LTCIC. Our data suggest that ex vivo-expanded CD34+ PBPCs might be able to allow long-term reconstitution of hematopoiesis.

Antigens, CD↗
PubMed1994

Cytokine therapy with gene-transfected cells: single injection of irradiated granulocyte-macrophage colony-stimulating factor-transduced cells accelerates hematopoietic recovery after cytotoxic chemotherapy in mice.

Development of cell-based delivery systems that can release therapeutic levels of hematopoietic growth factors into the systemic circulation would facilitate treatment of patients requiring cytokine therapy. In this study, we have investigated the potential of granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, irradiated syngeneic murine cells to accelerate hematopoietic recovery after cytotoxic chemotherapy. As a model, CMS-5 fibrosarcoma cells, were transduced with a retroviral vector containing the murine GM-CSF cDNA. Transduced cells secreted 38 ng GM-CSF/10(6) cells in 24 hours. After irradiation, in vitro GM-CSF production initially increased up to fivefold and was measurable for about 2 weeks. One and 2 days after injection of irradiated, GM-CSF-secreting CMS-5 cells (N2/CMVGM-CSF/CMS5 # 6 cells) into mice, GM-CSF serum levels of 405 +/- 58 pg/mL and 183 +/- 36 pg/mL were measured, respectively. Serum levels were comparable with levels detected 3 hours after injection of 100 ng recombinant murine GM-CSF (rmGM-CSF) subcutaneously (90 pg/mL). Injection of N2/CMVGM-CSF/CMS5 # 6 cells in cyclophosphamide-treated mice was as effective in accelerating neutrophil recovery as twice daily subcutaneous injections of rmGM-CSF. These data suggest that irradiated hematopoietic growth factor-secreting cells might offer an alternative to parenteral injections of recombinant cytokines in the treatment of neutropenic patients.

Animals↗
PubMed1994

Positively selected autologous blood CD34+ cells and unseparated peripheral blood progenitor cells mediate identical hematopoietic engraftment after high-dose VP16, ifosfamide, carboplatin, and epirubicin.

To investigate the feasibility of peripheral blood CD34+ cell selection and to analyze CD34+ cell-mediated engraftment after high-dose chemotherapy, we performed a phase I/II trial in 21 patients with advanced malignancies. The rationale for the selection of CD34+ cells from peripheral blood progenitor cell (PBPC) collections is based on the observation that contaminating tumor cells can be depleted approximately 3 logs using this procedure. CD34+ cells from chemotherapy+granulocyte colony-stimulating factor-mobilized PBPCs were positively selected with an avidin-biotin immunoadsorption column (CEPRATE SC system). One leukapheresis product with a median number of 2.8 x 10(6) CD34+ cells/kg was labeled with a biotinylated anti-CD34 monoclonal antibody and subsequently processed over the column. The yield of selected CD34+ cells was 73% +/- 24.6%. The purity of the CD34+ cell fraction was 61.4% +/- 19.7%. CD34+ cells were shown to represent predominantly committed progenitors coexpressing CD33, CD38, and HLA-DR molecules (lin+). They gave rise to myeloid as well as erythroid and multilineage colonies in vitro. In addition, positively selected CD34+ cells also comprised early hematopoietic progenitor cells, as shown by the presence of CD34+/lin- cells. Transfusion of positively selected CD34+ cells (2.5 x 10(6) CD34+/kg; range, 0.45 to 5.1) after high-dose VP16 (1,500 mg/m2), ifosfamide (12 g/m2), carboplatin (750 mg/m2), and epirubicin (150 mg/m2) (VIC-E) in 15 patients resulted in a rapid and stable engraftment of hematopoiesis without any adverse events. As compared with 13 historical control patients reconstituted with a comparable number of unseparated PBPCs, time to neutrophil and platelet recovery was identical in both groups (absolute neutrophil count > 500/microL, day + 12; platelet count > 50,000/microL, day + 15). These data indicate that autologous peripheral blood CD34+ cells and unseparated PBPCs mediate identical reconstitution of hematopoiesis after high-dose VIC-E chemotherapy. Because positive selection of CD34+ cells from mobilized blood results in a median 403-fold depletion of T cells, allogeneic CD34+ cells from mobilized blood should be investigated as an alternative to bone marrow cells for allotransplantation.

Adult↗
PubMed1993

Sulfotransferase-mediated mutagenicity of 1-hydroxymethylpyrene and 4H-cyclopenta[def]chrysen-4-ol and its enhancement by chloride anions.

1-Hydroxymethylpyrene (HMP), a primary benzylic alcohol, and 4H-cyclopenta[def]chrysen-4-ol (OH-CPC), a secondary benzylic alcohol, were investigated for mutagenicity in Salmonella typhimurium (reversion of the his- strain TA98) in the presence of various xenobiotic-metabolizing systems. In the direct test, HMP was inactive and OH-CPC was very weakly active. In the presence of NADPH-fortified postmitochondrial fraction from rat liver (S9/NADPH), no activation of OH-CPC was observed, whereas strong mutagenic effects were elicited by HMP. In the presence of cytosol and 3'-phosphoadenosine-5'-phosphosulfate (PAPS), both alcohols were activated to potent mutagens. For equal mutagenic effects, approximately 650-fold lower concentrations of HMP were required in the cytosol/PAPS-mediated assay than in the S9/NADPH-mediated assay. The cytosol/PAPS-mediated mutagenicity of both alcohols was 3- to 4-fold enhanced, when KCl (125 mM) was present during the exposure. The authentic chloromethylarenes, 1-chloromethylpyrene and 4-chloro-4H-cyclopenta[def]chrysene, showed very strong direct mutagenicity. These results, taken together with previous findings, indicate that both primary and secondary benzylic alcohols derived from polycyclic aromatic hydrocarbons may be activated by sulfotransferases to electrophilic sulfuric acid esters, and by subsequent substitution reaction to further active species such as benzylic chlorides.

Chrysenes↗