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S J Collins

Publications and source records attributed to S J Collins.

At least 37 records · Page 2Linked to original sources
PubMed2001

Transmissible spongiform encephalopathies in Australia.

The Australian National Creutzfeldt-Jakob Disease Registry (ANCJDR) commenced surveillance in September 1993 as part of the Commonwealth's response to 4 cases of pituitary hormone (gonadotrophin)-associated Creutzfeldt-Jakob disease (CJD). With the passage of time, the Registry has become responsible for ascertaining all human transmissible spongiform encephalopathies (TSE; also known as prion diseases) within Australia since 1970. Included in the spectrum of diseases monitored are classical (sporadic, genetic, and health care acquired) CJD, and variant CJD (vCJD), first reported in 1996 in the United Kingdom. Variant CJD has not yet been diagnosed in Australia. Final classification of persons with suspected human prion disease is based upon all available clinical, investigational and pathological information. Ascertainment methods are diverse and include prompted, half-yearly personal communications from neurologists and neuropathologists, death certificate searches, and morbidity separation coding searches of major hospital, and State and Territory databases. More recently, referral for diagnostic CSF 14-3-3 protein testing (performed by the ANCJDR) has considerably increased prospective notifications of suspect cases. As at September 2001 there were 460 cases on the register; 237 definite cases, 168 probable and 55 incomplete cases awaiting final classification.

Animals↗
PubMed2000

Iatrogenic Creutzfeldt-Jakob disease at the millennium.

The causes and geographic distribution of 267 cases of iatrogenic Creutzfeldt-Jakob disease (CJD) are here updated at the millennium. Small numbers of still-occurring cases result from disease onsets after longer and longer incubation periods following infection by cadaveric human growth hormone or dura mater grafts manufactured and distributed before the mid-1980s. The proportion of recipients acquiring CJD from growth hormone varies from 0.3 to 4.4% in different countries, and acquisition from dura mater varies between 0.02 and 0.05% in Japan (where most cases occurred). Incubation periods can extend up to 30 years, and cerebellar onsets predominate in both hormone and graft recipients (in whom the site of graft placement had no effect on the clinical presentation). Homozygosity at codon 129 of the PRNP gene is over-represented in both forms of disease; it has no effect on the incubation period of graft recipients, but may promote shorter incubation periods in hormone cases. Knowledge about potential high-risk sources of contamination gained during the last quarter century, and the implementation of methods to circumvent them, should minimize the potential for iatrogenic contributions to the current spectrum of CJD.

Creutzfeldt-Jakob Syndrome↗
PubMed2000

All-trans retinoic acid enhances the long-term repopulating activity of cultured hematopoietic stem cells.

The retinoic acid receptor (RAR) agonist, all-trans retinoic acid (ATRA), is a potent inducer of terminal differentiation of malignant promyelocytes, but its effects on more primitive hematopoietic progenitors and stem cells are less clear. We previously reported that pharmacologic levels (1 micromol) of ATRA enhanced the generation of colony-forming cell (CFC) and colony-forming unit-spleen (CFU-S) in liquid suspension cultures of lin- c-kit+ Sca-1+ murine hematopoietic precursors. In this study, we further investigated the effects of ATRA as well as an RAR antagonist, AGN 193109, on the generation of transplantable cells, including pre-CFU-S, short-term repopulating stem cells (STRCs), and long-term repopulating stem cells (LTRCs). ATRA enhanced the ex vivo maintenance and production of competitive repopulating STRCs and LTRCs from lin- c-kit+ Sca-1+ cells cultured in liquid suspension for 14 days. In addition, ATRA prevented the differentiation of these primitive stem cells into more mature pre-CFU-S during the 14 days of culture. In marked contrast, lin- c-kit+ Sca-1+ cells cultured with AGN 193109 for 7 days had virtually no short- or long-term repopulating ability, but displayed an approximately 6-fold increase in the pre-CFU-S population. The data suggest that the RAR agonist ATRA enhances the maintenance and self-renewal of short- and long-term repopulating stem cells. In contrast, the RAR antagonist AGN 193109 abrogates reconstituting ability, most likely by promoting the differentiation of the primitive stem cells. These results imply an important and unexpected role of retinoids in regulating hematopoietic stem cell differentiation. (Blood. 2000;95:470-477)

Animals↗
PubMed2000

Successful treatment of severe hemorrhagic cystitis with cystectomy following matched donor allogeneic hematopoietic cell transplantation.

We report a case of severe hemorrhagic cystitis complicating high-dose cyclophosphamide (CY), total body irradiation and allogeneic hematopoietic stem cell transplantation (HSCT). Supportive care with i.v. hydration, platelet transfusions, continuous bladder irrigation and aluminum irrigation of the bladder was ineffective and the patient developed multiple complications from hemorrhagic cystitis. His condition became critical with persistent bleeding, pulmonary edema and acute renal failure. These problems resolved following successful simple cystectomy and ileal conduit. The patient did not develop any acute or chronic complications following surgery. He is alive with a good quality of life and in third remission after receiving salvage chemotherapy 14 months after his transplantation.

Cyclophosphamide↗
PubMed1999

Negative transcriptional regulation mediated by thyroid hormone response element 144 requires binding of the multivalent factor CTCF to a novel target DNA sequence.

DNA target sites for a "multivalent" 11-zinc-finger CCTC-binding factor (CTCF) are unusually long ( approximately 50 base pairs) and remarkably different. In conjunction with the thyroid receptor (TR), CTCF binding to the lysozyme gene transcriptional silencer mediates the thyroid hormone response element (TRE)-dependent transcriptional repression. We tested whether other TREs, which in addition to the presence of a TR binding site require neighboring sequences for transcriptional function, might also contain a previously unrecognized binding site(s) for CTCF. One such candidate DNA region, previously isolated by Bigler and Eisenman (Bigler, J., and Eisenman, R. N. (1995) EMBO J. 14, 5710-5723), is the TRE-containing genomic element 144. We have identified a new CTCF target sequence that is adjacent to the TR binding site within the 144 fragment. Comparison of CTCF recognition nucleotides in the lysozyme silencer and in the 144 sequences revealed both similarities and differences. Several C-terminal CTCF zinc fingers contribute differently to binding each of these sequences. Mutations that eliminate CTCF binding impair 144-mediated negative transcriptional regulation. Thus, the 144 element provides an additional example of a functionally significant composite "TRE plus CTCF binding site" regulatory element suggesting an important role for CTCF in cooperation with the steroid/thyroid superfamily of nuclear receptors to mediate TRE-dependent transcriptional repression.

Animals↗
PubMed1999

All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1(+)) while enhancing the terminal maturation of committed granulocyte/monocyte progenitors.

All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of malignant promyelocytes, but its effects on more primitive hematopoietic progenitors and stem cells are less clear. In this study, we investigated the effect of ATRA on highly enriched murine hematopoietic precursor cells (lin-c-kit+Sca-1(+)) grown in liquid suspension culture for 28 days. ATRA initially slowed the growth of these hematopoietic precursors but prolonged and markedly enhanced their colony-forming cell production compared with the hematopoietic precursors cultured in its absence. At 7 and 14 days of culture, a substantially greater percentage of cells cultured with ATRA did not express lineage-associated antigens (55.4% at day 7 and 68.6% at day 14) and retained expression of Sca-1 (44.7% at day 7 and 79.9% at day 14) compared with cells grown in its absence (lin- cells: 31.5% at day 7 and 4% at day 14; Sca-1(+): 10.4% at day 7 and 0.7% at day 14). Moreover, a marked inhibition of granulocyte production was observed in cultures continuously incubated with ATRA. Significantly, ATRA markedly prolonged and enhanced the production of transplantable colony-forming unit-spleen (CFU-S) during 14 days of liquid suspension culture. In contrast with its effects on primitive lin-c-kit+Sca-1(+) hematopoietic precursors, ATRA did not exert the same effects on the more committed lin-c-kit+Sca-1(-) progenitor cells. Moreover, the late addition of ATRA (7 days post-culture initiation) to cultures of primitive hematopoietic precursors resulted in a marked decrease in colony-forming cell production in these cultures, which was associated with enhanced granulocyte differentiation. These observations indicate that ATRA has different effects on hematopoietic cells depending on their maturational state, preventing and/or delaying the differentiation of primitive hematopoietic precursors while enhancing the terminal differentiation of committed granulocyte/monocyte progenitors.

Animals↗
PubMed1999

Familial prion disease mutation alters the secondary structure of recombinant mouse prion protein: implications for the mechanism of prion formation.

A considerable body of data supports the model that the infectious agent (called a prion) which causes the transmissible spongiform encephalopathies is a replicating polypeptide devoid of nucleic acid. Prions are believed to propagate by changing the conformation of the normal cellular prion protein (PrPc) into an infectious isoform without altering the primary sequence. Proteins equivalent to the mature form of the wild-type mouse prion protein (residues 23-231) or with a mutation equivalent to that associated with Gerstmann-Straüssler-Scheinker disease (proline to leucine at codon 102 in human; 101 in mouse) were expressed in E. coli. The mutation did not alter the relative proteinase K susceptibility properties of the mouse prion proteins. The wild-type and mutant proteins were analyzed by circular dichroism under different pH and temperature conditions. The mutation was associated with a decrease in alpha-helical content, while the beta-sheet content of the two proteins was unchanged. This suggests the mutation, while altering the secondary structure of PrP, is not sufficient to induce proteinase K resistance and could therefore represent an intermediate isoform along the pathway toward prion formation.

Amino Acid Substitution↗
PubMed1999

D3: a gene induced during myeloid cell differentiation of Linlo c-Kit+ Sca-1(+) progenitor cells.

In an effort to characterize molecular events contributing to lineage commitment and terminal differentiation of stem/progenitor cells, we have used differential display reverse transcription polymerase chain reaction (DDRT-PCR) and cell lines blocked at two distinct stages of differentiation. The cell lines used were EML, which is representative of normal multipotential primitive progenitors (Sca-1(+), CD34(+), c-Kit+, Thy-1(+)) able to differentiate into erythroid, myeloid, and B-lymphoid cells in vitro, and MPRO, which is a more committed progenitor cell line, with characteristics of promyelocytes able to differentiate into granulocytes. One clone isolated by this approach was expressed in MPRO but not in EML cells and contained sequence identical to the 3' untranslated region of D3, a gene cloned from activated peritoneal macrophages of unknown function. We have observed a novel pattern of D3 gene expression and found that D3 is induced in EML cells under conditions that promote myeloid cell differentiation (interleukin-3 [IL-3], stem cell factor [SCF], and all-trans-retinoic acid [atRA]) starting at 2 days, corresponding to the appearance of promyelocytes. D3 RNA expression reached a maximum after 5 days, corresponding to the appearance of neutrophilic granulocytes and macrophages, and decreased by day 6 with increased numbers of differentiated neutrophils and macrophages in vitro. Induction of D3 RNA in EML was dependent on IL-3 and was not induced in response to SCF or atRA alone or SCF in combination with 15 other hematopoietic growth factors (HGF) tested. Similarly, D3 was not expressed in the normal bone marrow cell (BMC) counterpart of EML cells, Linlo c-Kit+ Sca-1(+) progenitor cells. D3 RNA expression was induced in these cells when cultured for 7 days in IL-3 plus SCF. A comparison of the expression of D3 RNA in cell lines and normal BMC populations demonstrated that D3 is induced during macrophage and granulocyte differentiation and suggests a potential physiological role for D3 in normal myeloid differentiation.

Animals↗
PubMed1999

Prion protein-deficient neurons reveal lower glutathione reductase activity and increased susceptibility to hydrogen peroxide toxicity.

The prion protein (PrP) has a central role in the pathogenesis of transmissible spongiform encephalopathies (TSE). Accumulating evidence suggests that normal cellular PrP (PrP(c)) may be involved in copper homeostasis and modulation of copper/zinc superoxide dismutase (Cu/ZnSOD) activity in neurons. Hydrogen peroxide (H(2)O(2)) is a toxic reactive oxygen species generated through normal cellular respiration, and neurons contain two important peroxide detoxifying systems (glutathione pathway and catalase). To determine whether PrP expression affects neuronal resistance to H(2)O(2), we exposed primary cerebellar granule neuron cultures derived from PrP knockout (PrP(-/-)) and wild-type (WT) mice to H(2)O(2) for 3, 6, and 24 hours. The PrP(-/-) neurons were significantly more susceptible to H(2)O(2) toxicity than WT neurons after 6 and 24 hours' exposure. The increased H(2)O(2) toxicity may be related to a significant decrease in glutathione reductase activity measured in PrP(-/-) neurons both in vitro and in vivo. This was supported by the finding that inhibition of GR activity with 1,3-bis(2-chloroethyl)-1-nitrosurea (BCNU) increased H(2)O(2) toxicity in WT neurons over the same exposure period. The PrP toxic peptide PrP106-126 significantly reduced neuronal glutathione reductase activity and increased susceptibility to H(2)O(2) toxicity in neuronal cultures suggesting that PrP toxicity in vivo may involve altered glutathione reductase activity. Our results suggest the pathophysiology of prion diseases may involve perturbed PrP(c) function with increased vulnerability to peroxidative stress.

Animals↗
PubMed1999

The hydrophobic core sequence modulates the neurotoxic and secondary structure properties of the prion peptide 106-126.

The neurodegeneration seen in spongiform encephalopathies is believed to be mediated by protease-resistant forms of the prion protein (PrP). A peptide encompassing residues 106-126 of human PrP has been shown to be neurotoxic in vitro. The neurotoxicity of PrP106-126 appears to be dependent upon its adoption of an aggregated fibril structure. To examine the role of the hydrophobic core, AGAAAAGA, on PrP106-126 toxicity, we performed structure-activity analyses by substituting two or more hydrophobic residues for the hydrophilic serine residue to decrease its hydrophobicity. A peptide with a deleted alanine was also synthesized. We found all the peptides except the deletion mutant were no longer toxic on mouse cerebellar neuronal cultures. Circular dichroism analysis showed that the nontoxic PrP peptides had a marked decrease in beta-sheet structure. In addition, the mutants had alterations in aggregability as measured by turbidity, Congo red binding, and fibril staining using electron microscopy. These data show that the hydrophobic core sequence is important for PrP106-126 toxicity probably by influencing its assembly into a neurotoxic structure. The hydrophobic sequence may similarly affect aggregation and toxicity observed in prion diseases.

Alanine↗
PubMed1999

Retinoic acid and 4-hydroxyphenylretinamide induce growth inhibition and tissue transglutaminase through different signal transduction pathways in mouse fibroblasts (NIH 3T3 cells).

4-Hydroxyphenylretinamide (4-HPR) is a synthetic retinoid with minimal toxicity and favorable pharmacokinetics during long-term administration to patients in clinical trials. Since 4-HPR binds poorly to the retinoic acid receptors, the issue of whether 4-HPR exerts its biological actions via classical retinoid receptor pathways remains to be resolved. We have previously reported that stable expression of a truncated retinoic acid receptor alpha, RARalpha403, transduced in NIH 3T3 cells by a retroviral vector, rendered the cells resistant to retinoic acid for growth inhibition and induction of tissue transglutaminase (TGase II). Here, we report that stable expression of the dominant negative construct RARalpha403 fails to blunt growth inhibition and TGase II induction by 4-HPR, a potent chemopreventive retinoid, in the same cells. These data show that retinoic acid receptors do not mediate either growth inhibition or induction of TGase II activity by 4-HPR in mouse fibroblast cells.

3T3 Cells↗
PubMed1999

Retinoid X receptor (RXR) agonist-induced activation of dominant-negative RXR-retinoic acid receptor alpha403 heterodimers is developmentally regulated during myeloid differentiation.

The multiple biologic activities of retinoic acid (RA) are mediated through RAR and retinoid X receptor (RXR) nuclear receptors that interact with specific DNA target sequences as heterodimers (RXR-RAR) or homodimers (RXR-RXR). RA receptor activation appears critical to regulating important aspects of hematopoiesis, since transducing a COOH-terminally truncated RARalpha exhibiting dominant-negative activity (RARalpha403) into normal mouse bone marrow generates hematopoietic growth factor-dependent cell lines frozen at the multipotent progenitor (EML) or committed promyelocyte (MPRO) stages. Nevertheless, relatively high, pharmacological concentrations of RA (1 to 10 microM) overcome these differentiation blocks and induce terminal granulocytic differentiation of the MPRO promyelocytes while potentiating interleukin-3 (IL-3)-induced commitment of EML cells to the granulocyte/monocyte lineage. In the present study, we utilized RXR- and RAR-specific agonists and antagonists to determine how RA overcomes the dominant-negative activity of the truncated RARalpha in these different myeloid developmental stages. Unexpectedly, we observed that an RXR-specific, rather than an RAR-specific, agonist induces terminal granulocytic differentiation of MPRO promyelocytes, and this differentiation is associated with activation of DNA response elements corresponding to RAR-RXR heterodimers rather than RXR-RXR homodimers. This RXR agonist activity is blocked by RAR-specific antagonists, suggesting extensive cross-talk between the partners of the RXR-RARalpha403 heterodimer. In contrast, in the more immature, multipotent EML cells we observed that this RXR-specific agonist is inactive either in potentiating IL-3-mediated commitment of EML cells to the granulocyte lineage or in transactivating RAR-RXR response elements. RA-triggered GALdbd-RARalpha hybrid activity in these cells indicates that the multipotent EML cells harbor substantial nuclear hormone receptor coactivator activity. However, the histone deacetylase (HDAC) inhibitor trichostatin A readily activates an RXR-RAR reporter construct in the multipotent EML cells but not in the committed MPRO promyelocytes, indicating that differences in HDAC-containing repressor complexes in these two closely related but distinct hematopoietic lineages might account for the differential activation of the RXR-RARalpha403 heterodimers that we observed at these different stages of myeloid development.

Cell Differentiation↗
PubMed1999

Retinoic acid-mediated G1-S-phase arrest of normal human mammary epithelial cells is independent of the level of p53 protein expression.

Retinoids mediate the normal growth of a variety of epithelial cells and may play an important role in the chemoprevention of breast cancer. Despite the widespread clinical use of retinoids, specific target genes that are regulated by retinoids are relatively poorly characterized. We reported previously that all-trans-retinoic acid (ATRA) mediates G1-S-phase arrest in normal human mammary epithelial cells (HMECs). The tumor suppressor gene p53 is thought to be a critical regulator of G1-S-phase arrest mediated by DNA-damaging agents such as chemotherapy and radiation. The role of p53 protein expression in G1-S-phase arrest mediated by the differentiating agent ATRA is unknown. Increased expression of p53 protein is observed in ATRA-treated HMECs at 72 h; however, initiation of G1-S-phase arrest starts at 24 h, suggesting that this observed induction of p53 is a secondary event. Using retroviral-mediated gene transfer, we expressed the E6 protein of the human papillomavirus strain 16 (HPV-16) in HMECs. The HPV-16 E6 protein binds to p53 and targets it for degradation. Western analysis confirmed that HPV-16 E6-transduced HMECs had markedly decreased levels of p53 protein expression. Suppression of cellular p53 levels in HMECs did not alter the sensitivity of HMECs to ATRA-mediated growth arrest. Our studies suggest that ATRA-mediated G1-S-phase arrest is independent of the level of p53 protein expression. We also tested the ability of estrogen and antiestrogens to induce growth arrest in HMECs lacking p53 expression and found no decrease in the sensitivity of these cells to these agents. Our results emphasize the chemotherapeutic potential of ATRA and antiestrogens, particularly for suppressing the growth of tumors lacking functional p53.

Antigens, Viral↗
PubMed1998

A widely expressed transcription factor with multiple DNA sequence specificity, CTCF, is localized at chromosome segment 16q22.1 within one of the smallest regions of overlap for common deletions in breast and prostate cancers.

The cellular protooncogene MYC encodes a nuclear transcription factor that is involved in regulating important cellular functions, including cell cycle progression, differentiation, and apoptosis. Dysregulated MYC expression appears critical to the development of various types of malignancies, and thus factors involved in regulating MYC expression may also play a key role in the pathogenesis of certain cancers. We have cloned one such MYC regulatory factor, termed CTCF, which is a highly evolutionarily conserved-11-zinc finger transcriptional factor possessing multiple DNA sequence specificity. CTCF binds to a number of important regulatory regions within the 5' noncoding sequence of the human MYC oncogene, and it can regulate its transcription in several experimental systems. CTCF mRNA is expressed in cells of multiple different lineages. Enforced ectopic expression of CTCF inhibits cell growth in culture. Southern blot analyses and fluorescence in situ hybridization (FISH) with normal human metaphase chromosomes showed that the human CTCF is a single-copy gene situated at chromosome locus 16q22. Cytogenetic studies have pointed out that chromosome abnormalities (deletions) at this locus frequently occur in many different human malignancies, suggesting the presence of one or more tumor suppressor genes in the region. To narrow down their localization, several loss of heterozygosity (LOH) studies of chromosome arm 16q in sporadic breast and prostate cancers have been carried out to define the most recurrent and smallest region(s) of overlap (SRO) for commonly deleted chromosome arm 16q material. For CTCF to be considered as a candidate tumor suppressor gene associated with tumorigenesis, it should localize within one of the SROs at 16q. Fine-mapping of CTCF has enabled us to assign the CTCF gene to about a 2 centiMorgan (cM) interval of 16q22.1 between the somatic cell hybrid breakpoints CY130(D) and CY4, which is between markers D16S186 (16AC16-101) and D16S496 (AFM214zg5). This relatively small region, containing the CTCF gene, overlaps the most frequently observed SROs for common chromosomal deletions found in sporadic breast and prostate tumors. In one of four analyzed paired DNA samples from primary breast cancer patients, we have detected a tumor-specific rearrangement of CTCF exons encoding the 11-zinc-finger domain. Therefore, taken together with other CTCF properties, localization of CTCF to a narrow cancer-associated chromosome region suggests that CTCF is a novel candidate tumor suppressor gene at 16q22.1.

Breast Neoplasms↗
PubMed1997

Inhibition of retinoic acid receptor function in normal human mammary epithelial cells results in increased cellular proliferation and inhibits the formation of a polarized epithelium in vitro.

The expression of retinoic acid receptor-beta (RAR beta) mRNA is absent or down-regulated in a majority of breast cancers, suggesting that loss of retinoic acid receptor function may be a critical event in breast cancer carcinogenesis. We developed an in vitro system to investigate whether the loss of retinoic acid receptor (RAR) function might affect the proliferation and structural differentiation of normal cultured human mammary epithelial cells (HMECs). Utilizing a truncated retinoic acid receptor (RAR)-alpha construct exhibiting dominant-negative activity against retinoic acid receptor isoforms alpha, beta, and gamma (DNRAR), we inhibited normal retinoic acid receptor function in HMECs. Suppression of RAR function in HMECs resulted in reduced growth inhibition mediated by all-trans-retinoic acid (ATRA). Moreover, the doubling time of HMECs expressing the DNRAR was significantly shortened, associated with a decrease in the percentage of cells in G1 and an increase in the percentage of cells in S-phase relative to controls. In addition, HMECs expressing the DNRAR cultured in prepared extracellular matrix exhibited a loss of extracellular matrix-induced growth arrest and formation of a polarized ductal epthelium. Our results suggest that ATRA and RARs may play an important role in regulating the proliferation of HMECs and in promoting differentiation.

Breast↗
PubMed1997

Novel measurement for automated interference pattern analysis of the diaphragm.

The automated interference pattern analysis for limb muscles was modified to take into account the unique features of the needle EMG of the diaphragm. The modification was successful in recording more accurately the number of small and large segments and the activity levels with inspiratory effort. "Clouds" were generated in ten healthy subjects. The techniques may prove useful in electrophysiological investigations.

Diaphragm↗
PubMed1997

Alterations of differentiation, clonal proliferation, cell cycle progression and bcl-2 expression in RAR alpha-altered sublines of HL-60.

All-trans retinoic acid (RA) induces granulocytic differentiation of acute promyelocytic leukemia cells both in vivo and in vitro. In the HL-60 wild-type (WT) early promyelocytic leukemia cell line, granulocytic differentiation appears to be directly mediated by the nuclear receptor RAR alpha. An HL-60 subline resistant to RA (HL-60 R) contains a point mutation which results in a truncation of 52 amino acids at the COOH end of RAR alpha. Cross-talk between differentiation, clonal inhibition of growth and apoptosis was studied using HL-60 WT, HL-60 R, and HL-60 R infected by a retroviral vector containing RAR alpha (LX) as targets, which were cultured with various retinoids, vitamin D3 analogs, HMBA, or DMSO. None of these compounds induced significant differentiation of HL-60 R and HL-60 LX, but they did induce differentiation of HL-60 WT. In contrast, retinoids inhibited the clonal proliferation of HL-60 WT, HL-60 R, and HL-60 LX. Vitamin D3 analogs including KH1060 stimulated the clonal growth of HL-60 R; but they inhibited clonal growth of HL-60 WT and LX. Levels of Bcl-2 strongly decreased in HL-60 WT and LX after treatment by retinoids, while no change in expression occurred in HL-60 R. Neither KH 1060 nor 9-cis RA induced apoptosis of HL-60 R, but these agents did induce apoptosis in HL-60 LX WT. Taken together, we showed that HL-60 R has a global defect in its ability to be induced to differentiate by a variety of pathways, not merely the retinoid pathway. Furthermore, our HL-60 models showed that inhibition of proliferation and induction of apoptosis and differentiation can be dissociated. Clinically, these results suggest that several putative differentiation agents may have anti-cancer (antiproliferative) activities, even though they do not induce differentiation of the cancer cells.

Antineoplastic Agents↗