Action of topoisomerase targeting drugs on non-Hodgkin's lymphoma and leukemia. Correlation of clinical and cell culture studies.
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Acute Disease↗
Biomedical subjects
F Traganos
Publications and source records attributed to F Traganos.
Phase II evaluation of a high-dose mitoxantrone based induction regimen in untreated adults with acute myeloid leukemia.
To evaluate a regimen including high-dose mitoxantrone in previously untreated adults with AML, 45 patients aged 21-59 (median 41) were given cytarabine, 3 g/m2 days 1-5, mitoxantrone, 80 mg/m2 day 2 and etoposide, 150 mg/m2 days 1,3,5. Post-remission therapy consisted of 5 cycles combining the same agents at reduced doses. Complete remission was seen in 36 patients. The observed 3-year survival is 28%. Cytogenetic pattern and CD34 expression correlated with response and survival. Significant toxicity included myelosuppression, mucositis, diarrhea and hyperbilirubinemia. Ventricular ejection fraction was generally reduced, with clinical cardiac dysfunction in only 2 patients. This high-dose mitoxantrone combination can be administered to young adults with AML with tolerable toxicity and results comparable to those of other dose-intensive regimens.
Actuarial Analysis↗
Chinese herbal mixture PC SPES in treatment of prostate cancer (review).
The Chinese herbal preparation denoted PC SPES, a mixture consisting of extracts from eight herbs, is being used with increasing frequency by prostate cancer patients worldwide. Evidence has emerged that PC SPES is an effective modality that alleviates some symptoms in advanced prostate cancer in a significant proportion of patients including the cases that failed conventional therapy. This evidence as well as published data that show the effects of PC SPES in suppressing growth of prostate cancer in animal model studies, is reviewed together with the available data on the possible side effects of PC SPES. The review also covers in vitro studies that reveal the cell cycle specificity, induction of apoptosis, effects on androgen receptor and other molecular and metabolic changes induced by PC SPES that may explain its anticancer activity. Individual chemical components that are present in herbs of which PC SPES is composed, known to have anti-proliferative, antitumor, antimutagenic, analgesic and/or differentiation inducing activity, are listed and discussed. The effectiveness of PC SPES in prostate cancer is explained as due to its complex composition which may target many signal transduction and metabolic pathways simultaneously thereby eliminating the back-up or redundant mechanisms that otherwise promote cell survival when single-target agents are used.
Animals↗
Histone H3 phosphorylation in human monocytes and during HL-60 cell differentiation.
Phosphorylation of the nucleosome core histone H3 (H3) on Ser-10 is thought to be a prerequisite for chromatin condensation at mitosis. Although during interphase, cell differentiation, or mitogenic activation of quiescent cells, changes in chromatin structure that involve local chromatin condensation/decondensation also occur, little is known about H3 phosphorylation during these transitions. Using the recently developed sensitive marker to monitor H3 phosphorylation, namely, the mAb that recognizes the phosphorylated epitope of H3 (anti-H3-P mAb), the status of H3 phosphorylation was assayed in individual human lymphocytes after their mitogenic stimulation (G0 to G1 transition) and in human leukemic HL-60 cells induced to differentiate by all-trans-retinoic acid (RA), 1,25-dihydroxyvitamin D3 (vit D3), dimethyl sulfoxide (DMSO), or phorbol myristate acetate (PMA). Multiparameter flow cytometry was used to correlate H3 phosphorylation with cell cycle position. The specificity of the anti-H3-P mAb was confirmed by the loss of its binding following cell treatment with alkaline phosphatase. The presence of phosphorylated H3 was detected during interphase in HL-60 cells and in normal lymphocytes at a level severalfold lower than during mitosis. No significant changes in H3 phosphorylation were observed during lymphocyte stimulation. Unexpectedly, the level of H3 phosphorylation was over fourfold higher in monocytes than in lymphocytes or granulocytes from peripheral blood. The punctate pattern of labeling with anti-H3-P mAb in monocyte nuclei suggests that H3 is phosphorylated in small clusters of adjacent nucleosomes. Differentiation of HL-60 cells was accompanied by a rise in H3 phosphorylation, which was higher after induction by RA, vit D3, and PMA (approx. threefold) than after DMSO (approximately 20%). The data indicate that in addition to being a critical event during chromatin condensation at mitosis, H3 phosphorylation plays a role during chromatin changes accompanying differentiation of HL-60 cells, in particular, along the monocytic lineage. The high level of H3 phosphorylation in monocytes may serve as a marker of these cells and is being explored as a possible diagnostic and prognostic tool in monocytic leukemias.
Antibodies, Monoclonal↗
Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials.
Trans-resveratrol, a polyphenol present in red wines and various human foods, is an antioxidant also with reported chemopreventive properties. However, whether resveratrol may exert different effects in malignant cells with a common anatomical origin yet displaying different invasive characteristics is not known. Since invasiveness and metastasis are considered to be the most insidious and life-threatening aspects for all cancers, we compared the ability of resveratrol to control growth and cell cycle transition in the highly invasive MDA-MB-435 with the minimally invasive MCF-7 breast carcinoma cells. The data revealed that resveratrol exerted a greater inhibitory effect on the MDA-MB-435 cells. A diminution of percentage of cells in G1 phase and a corresponding accumulation of cells in S phase of the cell cycle was observed. We also studied the effect of resveratrol on a panel of MDA-MB-435 cells transfected with nm23-H1 and nm23-H2 genes, which have been suggested to play a role in controlling metastasis in breast cancer cells. These cells are designated as Vbeta, 1beta, 1Tbeta, 2beta, and 2Tbeta, respectively. The control Vbeta consists of MDA-MB-435 cells transfected with bacterial beta-glucuronidase. Cells labeled 1beta and 1Tbeta correspond to those carrying beta-glucuronidase and overexpressed wild-type (His118) or mutant (Tyr118, catalytically inactive) nm23-H1 genes. The 2beta and 2Tbeta refer to cells transfected with wild-type and mutant nm23-H2 genes. The responses of these cells to resveratrol were assessed by measuring proliferation, cell cycle phase distribution, and changes in expression of several genes. These studies have shown that resveratrol (25 microM, 3 days) reduced growth of all cell types by 60-80%. Overexpression of both wild-type and catalytically inactive nm23-H1 (1beta, 1Tbeta) but not nm23-H2 (2beta, 2Tbeta) reduced the proportion of cells in G1 phase, compared to the Vbeta control cells. Little changes in expression of PCNA, Rb, p53, and bcl-2 were observed in the five cell types treated with resveratrol, compared to untreated cells. Noted exceptions included reduced expression of Rb protein and increased expression of p53 in 2beta and 2Tbeta cells, and increased expression of bcl-2 in 2beta cells, treated with resveratrol. In contrast, resveratrol upregulated expression of cathepsin D by 50-100% in all cell lines except 1beta. These results suggest that the intrinsic metastatic potential of cancer cells may affect their responses to chemopreventive agents such as resveratrol.
Adenocarcinoma↗
Differences in induction of p53, p21WAF1 and apoptosis in relation to cell cycle phase of MCF-7 cells treated with camptothecin.
The DNA topoisomerase I (topI) inhibitor camptothecin (CPT), stabilizes so-called cleavable complexes which consist of topI covalently attached to 3' OH ends of DNA nicks. Collisions between the progressing DNA replication forks (occurring in S phase cells) or between the transcription driven RNA polymerase molecules (occurring in G1, S and G2 cells) and these complexes convert the latter into secondary DNA lesions which are unrepairable and lethal to the cell. Changes induced by CPT in the level of the tumor suppressor p53, cyclin-dependent kinase inhibitor p21WAF1 and proapoptotic protein Bax (all detected immunocytochemically), were measured separately in the nucleus and cytoplasm of individual human breast carcinoma MCF-7 cells by laser scanning cytometry (LSC) in relation to cell cycle position and induction of apoptosis. The initial transient cell arrest at the G1 checkpoint seen at 8-16 h of treatment with 0.15 microM CPT was accompanied by the rapid accumulation of p53 (preventable by cycloheximide) in the nucleus; the rise (>20-fold) in p53 was maximal for S phase cells. The magnitude of the nuclear p53 increase induced by CPT, at maximum, was 2-fold higher than that induced by the proteasome inhibitor N-acetyl-Leu-Leu-norleucinal (LLnL). While the accumulation of p53 was seen in all phases of the cycle, only G1 cells responded by induction ( approximately 60-fold increase) of p21WAF1. Inhibition of DNA replication by aphidicolin prevented the accumulation of p53 in S and G2/M but had no effect on its induction in G1 cells. Perturbation of cell progression through S phase was seen between 24-72 h of treatment, and it coincided with induction of Bax and apoptosis (both maximal in S phase cells). Thus, the changes observed in S phase cells (nuclear accumulation of p53 preventable by aphidicolin, induction of Bax, apoptosis), triggered by the collisions of DNA replication forks with the CPT-induced lesions, were distinct from the changes in G1 (nuclear p53 accumulation unaffected by aphidicolin, induction of p21WAF1) presumably triggered by collisions of RNA polymerase with the CPT-lesions. Great heterogeneity in expression of p53 and p21WAF1 of the G1 cell population in response to CPT was observed, which may reflect the intercellular variability in the rate of transcription (i.e., frequencies of collisions of RNA polymerase with the lesions). Thus, differences in the transcriptional activity of G1 cells may play a role in their sensitivity to CPT and similar topI inhibitors.
Apoptosis↗
Histone H3 phosphorylation and expression of cyclins A and B1 measured in individual cells during their progression through G2 and mitosis.
Phosphorylation of histone H3 (H3) on Ser-10 correlates with chromatin condensation at mitosis. A new monoclonal antibody (anti-H3-P) was developed that recognizes phosphorylated H3 (H3-P). This antibody was used in multiparameter flow cytometric analysis to relate H3 phosphorylation in individual human leukemic cells to the cells' position in the cycle as well as their expression of cyclins A and B1. Mitotic cells, from prophase to telophase, reacted with anti-H3-P; the binding of the antibody to chromatin of interphase cells was several times weaker. Cell growth in the presence of staurosporine, an inhibitor of the kinase(s) that phosphorylate H3, abolished the cells' reactivity with the antibody. The reactivity also was abolished by incubation of permeabilized mitotic cells with alkaline phosphatase. These data indicate that, within permeabilized cells, the antibody is indeed specific for H3-P and does not detect the unphosphorylated epitope. All cells reacting with anti-H3-P, with the exception of prophase and early prometaphase, were cyclin A negative; the expression of cyclin B1 in these cells was threefold higher than in G2 cells. The analysis of phosphorylation of H3 in individual cells when combined with multiparameter analysis of their cycle position and expression of other proteins offers new possibilities to study molecular mechanisms associated with the G2 to M transition and chromatin condensation. It also offers an assay to screen in vivo inhibitors of kinase(s) or phosphatase(s) involved in H3 phosphorylation or dephosphorylation, and it provides a valuable marker to identify mitotic cells by cytometry.
Alkaline Phosphatase↗
Measurement of apoptosis.
The cell dying by apoptosis undergoes a sequence of morphological, biochemical, and molecular changes which are characteristic, and often unique, to this mode of cell death. Specific features of apoptotic cells resulting from these changes, which serve as markers used to reveal the apoptotic mode of cell death and to quantify the extent of apoptosis in cultures or in tissue, are reviewed. Analysis of these features by flow or image cytometry is the most commonly used approach to detect, quantify, and study various aspects of apoptosis. Flow or laser scanning cytometry also offer all the advantages of rapid, accurate and multiparametric measurements to investigate the biological processes associated with cell death. Numerous methods have been developed to identify apoptotic and necrotic cells, which are widely used in various disciplines, particularly in oncology and immunology. The methods based on changes in cell morphology, plasma membrane molecular structure and transport function, function of cell organelles, DNA stability to denaturation and endonucleolytic DNA degradation are reviewed and their applicability in the research laboratory and in the clinical setting is discussed. The most common pitfalls and improper use of the methodology in analysis of cell death and in data interpretation are also discussed.
Animals↗
In vitro effects and clinical evaluation of a human chorionic gonadotrophin preparation in acute leukemia.
Commercial human chorionic gonadotrophin (HCG) preparations decrease the tumorigenicity of human tumors in immunodeficient mice and induce apoptotic cell death in animal tumor models. Preliminary studies in humans have demonstrated tumor regression in patients with Kaposi's sarcoma given intralesional injections of HCG. To further evaluate HCG's antitumor activity we conducted in vitro and clinical evaluations of HCG in acute myeloid leukemia (AML). In HL-60 leukemic cell lines, a 20-40% inhibition of cell density was demonstrated by trypan blue exclusion method at low concentrations of an HCG preparation (2 x 10(-3)-2 x 10(-2)). Similar concentrations also resulted in a reduction in the proportion of cells in G2M phase of the cell cycle, as well as enhanced differentiation compared to control cells. Fifteen patients with advanced AML with marrow blast counts >30%, and five with marrow blast counts between 10 and 26% were given daily subcutaneous injections of HCG 2-4 IU and oral levamisole 50 mg weekly. Five patients with absolute blast counts in the blood ranging from 0 to 3500/microl and percent blasts in the marrow ranging from 16 to 81% were observed to have no progressive increase in either marrow or peripheral blast counts for 70-121 days. One patient with a pretreatment blast count of 10% in the marrow, no circulating blasts and minor cytopenias had a decrease in marrow blasts to less than 5% which has persisted at 550 days. No significant improvement from baseline levels of neutrophils, hemoglobin or platelets were observed in any nl the patients treated. Increases in apoptotic cell death were observed in over 50% of patients' cells with some demonstrating peak levels similar to experiences in patients treated with DNA-damaging chemotherapy. A decreased expression of bcl-2 was seen in the majority of patients ranging from 6 to 62%. These new observations suggest that HCG preparations may inhibit leukemic cell growth through enhancement of cell death mechanisms and could be used in judicious combinations with other approaches. The results confirm the pro-apoptotic effects of HCG preparations reported in patients with Kaposi's sarcoma. Identification of the active component of HCG preparations and further understanding of its growth modulatory action will be important in its development as a clinically useful agent.
Acute Disease↗
Critical aspects in the analysis of apoptosis and necrosis.
Despite that large number of methods to analyze cell death, in particular apoptosis, that have been developed, identification of the mode of cell death and its quantitation is not always simple or straightforward. The difficulties, potential pitfalls and traps in quantitation of dead cells, whether apoptotic or necrotic are reviewed. The following are common flaws in the measurement of cell death, which include incorrect assumptions, erroneous data interpretation and shortcomings of the methodology: 1) Misclassification of apoptotic bodies or chromatin fragments as individual apoptotic cells based on cellular DNA content analysis by flow cytometry; 2) Assumption that the quantity of fragmented DNA extracted from cells represents the frequency of apoptosis; 3) Conjecture that the apoptotic index represents the cell death rate; 4) Assumption that apoptotic cells must exhibit classical features of apoptosis e.g. internucleosomal DNA fragmentation; 5) Inadequacy of methods that presume to discriminate between late apoptotic and necrotic cells; 6) Possibility of a selective enrichment or loss of apoptotic cells during cell separation on density gradients, during trypsinization or other procedures of cell collection; and 7) Inability to distinguish between live, nonapoptotic cells phagocytizing apoptotic bodies and genuine apoptotic cells by flow cytometric methods. Many of the problems stem from the difficulty in identifying apoptotic or necrotic cells. Because apoptosis and necrosis have been originally defined based on morphological criteria it is essential to confirm the mode of cell death by microscopy. Laser scanning cytometry (LSC), which combines the advantages of flow and image cytometry, offers the possibility of morphological examination of apoptotic cells. By virtue of this attribute LSC appears to be the instrument of choice for analysis of apoptosis.
Apoptosis↗
Immunoseparation and immunodetection of nucleic acids labeled with halogenated nucleotides.
A novel methodology for labeling, isolation, and detection of nucleic acids is described. Nucleic acid isolation is based on in vivo or in vitro incorporation of BrU or BrdU to either RNA or DNA, respectively, followed by immunoprecipitation of the labeled nucleic acid utilizing anti-BrdU MoAb, which crossreacts with BrU, attached to solid particles. Filter-bound bromine-labeled DNA or RNA was detected by immunoblotting with anti-BrdU MoAb, by a combined Southern/Western or Northern/Western approach, respectively. This method was applied to isolate and detect rRNA and mRNA from human cells, plasmid DNA from bacterial cells, and in vitro synthesized DNA. Newly transcribed BrU-labeled mRNA was recovered from the immunoprecipitates and analyzed by RT-PCR to study phorbol ester-mediated regulation of interleukin 1 gene transcription in human leukemic HL-60 or lymphoma U937 cells. The plasmid DNAs were isolated by immunoprecipitation from transformed bacterial cultures that were grown in the presence of BrdU and were detected immunochemically on filters. Likewise, the products of RT-PCR and Klenow polymerase-catalyzed DNA synthesis in which dTTP was replaced with BrdUTP were detected by immunoblotting. Since the method allows one to selectively separate or detect nucleic acids only synthesized during a pulse of the precursor, it can uniquely be used to identify nascent gene transcripts or the transcripts synthesized within specific time windows, e.g., after induction of differentiation, carcinogenesis, or drug treatment, and distinguish such transcripts from preexisting ones. In addition, this approach offers a simple and inexpensive alternative for preparing labeled DNA as well as RNA probes for use in a variety of hybridization protocols. Due to the low toxicity of BrU and BrdU, this approach can be used in analysis of gene transcription or DNA replication in vivo.
Antibodies, Monoclonal↗
Activation-induced expression of human programmed death-1 gene in T-lymphocytes.
The Programmed Death-1 (PD-1) gene is a member of the immunoglobulin superfamily of genes. Murine PD-1 mRNA expression has been shown to correlate with activation-induced apoptosis in a mouse T-cell hybridoma cell line and in murine thymocytes. Here we report that expression of the human homolog, hPD-1, seems to correlate with activation of T lymphocytes rather than apoptosis. We observed a time-dependent upregulation of hPD-1 mRNA and protein levels in Jurkat cells during phorbol ester (12-O-tetradecanoylphorbol 13-acetate, TPA)-induced differentiation. Human PD-1 protein was also induced during lectin-stimulated activation of human peripheral blood mononuclear cells. Additionally, TPA stimulation of Jurkat cells induces tyrosine phosphorylation of hPD-1, putatively on its cytoplasmic tail signal transduction motif. These data suggest a role for hPD-1 during activation and differentiation of T-lymphocytes.
Antigens, CD↗
Cytometry in cell necrobiology: analysis of apoptosis and accidental cell death (necrosis).
The term cell necrobiology is introduced to comprise the life processes associated with morphological, biochemical, and molecular changes which predispose, precede, and accompany cell death, as well as the consequences and tissue response to cell death. Two alternative modes of cell death can be distinguished, apoptosis and accidental cell death, generally defined as necrosis. The wide interest in necrobiology in many disciplines stems from the realization that apoptosis, whether it occurs physiologically or as a manifestation of a pathological state, is an active mode of cell death and a subject of complex regulatory processes. A possibility exists, therefore, to interact with the regulatory machinery and thereby modulate the cell's propensity to die in response to intrinsic or exogenous signals. Flow cytometry appears to be the methodology of choice to study various aspects of necrobiology. It offers all the advantages of rapid, multiparameter analysis of large populations of individual cells to investigate the biological processes associated with cell death. Numerous methods have been developed to identify apoptotic and necrotic cells and are widely used in various disciplines, in particular in oncology and immunology. The methods based on changes in cell morphology, plasma membrane structure and transport function, function of cell organelles, DNA stability to denaturation, and endonucleolytic DNA degradation are reviewed and their applicability in the research laboratory and in the clinical setting is discussed. Improper use of flow cytometry in analysis of cell death and in data interpretation also is discussed. The most severe errors are due to i) misclassification of nuclear fragments and individual apoptotic bodies as single apoptotic cells, ii) assumption that the apoptotic index represents the rate of cell death, and iii) failure to confirm by microscopy that the cells classified by flow cytometry as apoptotic or necrotic do indeed show morphology consistent with this classification. It is expected that flow cytometry will be the dominant methodology for necrobiology.
Apoptosis↗
In vivo and ex vivo study of metabolic and cellular effects of 5-fluorouracil chemotherapy in a mouse mammary carcinoma.
The effect of 5-fluorouracil (5FU) on the 31P nuclear magnetic resonance (NMR) profile of a mouse mammary carcinoma, implanted on the foot of CH3/He mice, was studied both in vivo and in perchloric acid extracts. In vivo, significant increases in the ratios, nucleotide triphosphate:inorganic phosphate (Pi) (p < 0.02) and phosphocreatine:Pi (p < 0.005), were observed 48 h after 5FU, relative to control. Two readily resolvable peaks were observed in the phosphomonoester region of the in vivo NMR spectrum, phosphocholine (PC) and a peak (denoted PME') comprised of mainly phosphoethanolamine (PE). PME':PC was significantly elevated relative to control from 24 h to 168 h (p < 0.0001 at 48 h). Perchloric acid extract data indicate that the change in this ratio was due to an increase in the PE concentration rather than a decrease in PC. PE increased from 0.56 +/- 0.11 micromol/g tissue in controls to 0.95 +/- 0.29 micromol/g tissue 48 h after 5FU (p < 0.006). Perchloric acid extracts also revealed a significant increase in phosphodiesters. Glycerophosphocholine increased from 0.82 +/- 0.24 micromol/g tissue in controls to 1.82 +/- 0.61 micromol/g tissue in 5FU treated tumors after 48 h (p < 0.002), and glycerophosphoethanolamine increased from 0.25 +/- 0.06 micromol/g tissue in controls to 0.36 +/- 0.10 micromol/g tissue in treated tumors (p < 0.004). These changes suggest that ethanolamine and choline containing metabolites in this tumor may be metabolized via different pathways. Cell cycle analysis showed only relatively small changes in cell cycle distribution and apoptotic fraction following 5FU.
Adenocarcinoma↗
Cell cycle specificity of apoptosis during treatment of leukaemias.
This review summarizes our observations on the mechanism of induction of apoptosis in vitro in leukaemic cell lines and in vivo in patients with leukaemia undergoing chemotherapy, in relation to the cell cycle. Multiparameter flow cytometric methods allowed us to identify apoptotic cells and position them with respect to their cell cycle phase. Several antitumor agents of different classes have been characterized in terms of the cell cycle phase specificity of induction of apoptosis. Three types of apoptosis could be distinguished in relation to the initial damage to the cell vis-a-vis cell cycle position: (1) homo-phase apoptosis where the cells underwent apoptosis during the same phase in which they were initially affected; (2) homo-cycle apoptosis, where the cells underwent apoptosis during the same cell cycle in which they were initially affected, i.e., prior to or during the first mitosis, and (3) post-mitotic apoptosis, where cells underwent apoptosis during the cell cycle(s) subsequent to that in which the cell was initially affected, most likely at the G1 or G2 checkpoints of these cycle(s). Four ranges of drug concentration can be distinguished in vitro for most drugs, where either: (1) no immediate effects; (2) cytostasis or post-mitotic apoptosis; (3) homo-cycle or homo-phase apoptosis; or (4) necrosis are observed. Analysis of cell death of blast cells from peripheral blood or bone marrow of over 250 leukaemia patients (AML, ALL, CML in blast crisis) treated with various drugs during routine chemotherapy reveals that in the case of DNA topoisomerase inhibitors (e.g., mitoxantrone, VP-16) apoptosis is often rapid (peaks at 1-2 days after drug administration) and has features of homo-phase apoptosis. In contrast, cell death observed after administration of paclitaxel (taxol) or cytarabine (cytosine arabinoside) occurs later and has features of post-mitotic apoptosis: the cells divide but die in G1 of the subsequent cycle(s).
Journal Article↗
Phase I clinical and laboratory evaluation of topotecan and cytarabine in patients with acute leukemia.
PURPOSE: To determine the maximal-tolerated dose (MTD) of topotecan with cytarabine in acute leukemia patients, and to evaluate leukemia cell apoptosis in these patients. PATIENTS AND METHODS: Fifty-three patients with acute leukemia not responsive to standard therapy were treated at eight dose levels of topotecan (2.5 mg/m2/d to 7.75 mg/m2/d). Topotecan was given as a 30-minute infusion daily with cytarabine 1 g/m2/d, both for 5 days. Using a flow-cytometric technique, the percent apoptotic cells in blood and bone marrow samples was determined, and the cell cycle distribution of the leukemic cells studied. RESULTS: Oropharyngeal mucositis was dose-limiting. The MTD of topotecan was 4.75 mg/m2/d for 5 days in high-risk patients and 7.0 mg/m2/d for 5 days in low-risk patients. The mean percent apoptotic cells in the peripheral blood reached a peak of 18.8%, a median of 48 hours following the first dose of topotecan. Patients with higher S-phase fractions, either before treatment or following cytarabine, were more likely to achieve bone marrow aplasia than those with lower S-phase fractions (P = .01 and P < .05, respectively). Clinical responses were seen in four of 39 patients with acute myelogenous leukemia (AML; of whom 32 had received prior high-dose cytarabine), three of six with acute lymphoblastic leukemia (ALL), and one of eight with chronic myelogenous leukemia in blast phase (CML-BP). CONCLUSION: The recommended phase II dose of topotecan with intermediate-dose cytarabine is 4.75 mg/m2/d for high-risk patients and 7.0 mg/m2/d for low-risk patients. The percentage of cells in S phase was important in determining response to treatment.
Adult↗
The cell cycle effects of camptothecin.
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Animals↗
Induction of apoptosis by camptothecin and topotecan.
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Antineoplastic Agents, Phytogenic↗