Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 43
Filter
1.
Nat Ecol Evol ; 6(11): 1710-1722, 2022 11.
Article in English | MEDLINE | ID: mdl-36163257

ABSTRACT

Protecting nature's contributions to people requires accelerating extinction risk assessment and better integrating evolutionary, functional and used diversity with conservation planning. Here, we report machine learning extinction risk predictions for 1,381 palm species (Arecaceae), a plant family of high socio-economic and ecological importance. We integrate these predictions with published assessments for 508 species (covering 75% of all palm species) and we identify top-priority regions for palm conservation on the basis of their proportion of threatened evolutionarily distinct, functionally distinct and used species. Finally, we explore palm use resilience to identify non-threatened species that could potentially serve as substitutes for threatened used species by providing similar products. We estimate that over a thousand palms (56%) are probably threatened, including 185 species with documented uses. Some regions (New Guinea, Vanuatu and Vietnam) emerge as top ten priorities for conservation only after incorporating machine learning extinction risk predictions. Potential substitutes are identified for 91% of the threatened used species and regional use resilience increases with total palm richness. However, 16 threatened used species lack potential substitutes and 30 regions lack substitutes for at least one of their threatened used palm species. Overall, we show that hundreds of species of this keystone family face extinction, some of them probably irreplaceable, at least locally. This highlights the need for urgent actions to avoid major repercussions on palm-associated ecosystem processes and human livelihoods in the coming decades.


Subject(s)
Arecaceae , Ecosystem , Animals , Humans , Conservation of Natural Resources , Endangered Species , Plants
2.
Nat Commun ; 9(1): 980, 2018 03 07.
Article in English | MEDLINE | ID: mdl-29515115

ABSTRACT

Substitutional donor atoms in silicon are promising qubits for quantum computation with extremely long relaxation and dephasing times demonstrated. One of the critical challenges of scaling these systems is determining inter-donor distances to achieve controllable wavefunction overlap while at the same time performing high fidelity spin readout on each qubit. Here we achieve such a device by means of scanning tunnelling microscopy lithography. We measure anti-correlated spin states between two donor-based spin qubits in silicon separated by 16 ± 1 nm. By utilising an asymmetric system with two phosphorus donors at one qubit site and one on the other (2P-1P), we demonstrate that the exchange interaction can be turned on and off via electrical control of two in-plane phosphorus doped detuning gates. We determine the tunnel coupling between the 2P-1P system to be 200 MHz and provide a roadmap for the observation of two-electron coherent exchange oscillations.

3.
J Evol Biol ; 29(11): 2143-2156, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27374779

ABSTRACT

We evaluated reproductive isolation in two species of palms (Howea) that have evolved sympatrically on Lord Howe Island (LHI, Australia). We estimated the strength of some pre- and post-zygotic mechanisms in maintaining current species boundaries. We found that flowering time displacement between species is consistent across in and ex situ common gardens and is thus partly genetically determined. On LHI, pre-zygotic isolation due solely to flowering displacement was 97% for Howea belmoreana and 80% for H. forsteriana; this asymmetry results from H. forsteriana flowering earlier than H. belmoreana and being protandrous. As expected, only a few hybrids (here confirmed by genotyping) at both juvenile and adult stages could be detected in two sites on LHI, in which the two species grow intermingled (the Far Flats) or adjacently (Transit Hill). Yet, the distribution of hybrids was different between sites. At Transit Hill, we found no hybrid adult trees, but 13.5% of younger palms examined there were of late hybrid classes. In contrast, we found four hybrid adult trees, mostly of late hybrid classes, and only one juvenile F1 hybrid in the Far Flats. This pattern indicates that selection acts against hybrids between the juvenile and adult stages. An in situ reciprocal seed transplant between volcanic and calcareous soils also shows that early fitness components (up to 36 months) were affected by species and soil. These results are indicative of divergent selection in reproductive isolation, although it does not solely explain the current distribution of the two species on LHI.


Subject(s)
Arecaceae , Hybridization, Genetic , Reproductive Isolation , Sympatry , Animals , Australia , Genotype
4.
J Evol Biol ; 29(8): 1472-87, 2016 Aug.
Article in English | MEDLINE | ID: mdl-27177130

ABSTRACT

Ecological speciation requires divergent selection, reproductive isolation and a genetic mechanism to link the two. We examined the role of gene expression and coding sequence evolution in this process using two species of Howea palms that have diverged sympatrically on Lord Howe Island, Australia. These palms are associated with distinct soil types and have displaced flowering times, representing an ideal candidate for ecological speciation. We generated large amounts of RNA-Seq data from multiple individuals and tissue types collected on the island from each of the two species. We found that differentially expressed loci as well as those with divergent coding sequences between Howea species were associated with known ecological and phenotypic differences, including response to salinity, drought, pH and flowering time. From these loci, we identified potential 'ecological speciation genes' and further validate their effect on flowering time by knocking out orthologous loci in a model plant species. Finally, we put forward six plausible ecological speciation loci, providing support for the hypothesis that pleiotropy could help to overcome the antagonism between selection and recombination during speciation with gene flow.


Subject(s)
Arecaceae/genetics , Genetic Speciation , Sympatry , Australia , Gene Flow , Islands
5.
J Evol Biol ; 26(4): 733-45, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23320532

ABSTRACT

On Lord Howe Island, speciation is thought to have taken place in situ in a diverse array of distantly related plant taxa (Metrosideros, Howea and Coprosma; Proc. Natl Acad. Sci. USA 108, 2011, 13188). We now investigate whether the speciation processes were driven by divergent natural selection in each genus by examining the extent of ecological and genetic divergence. We present new and extensive, ecological and genetic data for all three genera. Consistent with ecologically driven speciation, outlier loci were detected using genome scan methods. This mechanism is supported by individual-based analyses of genotype-environment correlations within species, demonstrating that local adaptation is currently widespread on the island. Genetic analyses show that prezygotic isolating barriers within species are currently insufficiently strong to allow further population differentiation. Interspecific hybridization was found in both Howea and Coprosma, and species distribution modelling indicates that competitive exclusion may result in selection against admixed individuals. Colonization of new niches, partly fuelled by the rapid generation of new adaptive genotypes via hybridization, appears to have resulted in the adaptive radiation in Coprosma - supporting the 'Syngameon hypothesis'.


Subject(s)
Adaptation, Biological , DNA, Plant/genetics , Genetic Speciation , Genome, Plant , Amplified Fragment Length Polymorphism Analysis , Arecaceae/genetics , Arecaceae/physiology , Australia , DNA, Plant/analysis , Ecosystem , Genetic Loci , Genetic Variation , Genetics, Population , Genotype , Hybridization, Genetic , Islands , Models, Biological , Myrtaceae/genetics , Myrtaceae/physiology , Plant Leaves/genetics , Reproductive Isolation , Rubiaceae/genetics , Rubiaceae/physiology , Selection, Genetic
6.
Phys Rev Lett ; 108(26): 267601, 2012 Jun 29.
Article in English | MEDLINE | ID: mdl-23005015

ABSTRACT

Polaron pairs are intermediate electronic states that are integral to the optoelectronic conversion process in organic semiconductors. Here, we report on electrically detected spin echoes arising from direct quantum control of polaron pair spins in an organic light-emitting diode at room temperature. This approach reveals phase coherence on a microsecond time scale, and offers a direct way to probe charge recombination and dissociation processes in organic devices, revealing temperature-independent intermolecular carrier hopping on slow time scales. In addition, the long spin phase coherence time at room temperature is of potential interest for developing quantum-enhanced sensors and information processing systems which operate at room temperature.

7.
Nat Commun ; 3: 898, 2012 Jun 12.
Article in English | MEDLINE | ID: mdl-22692541

ABSTRACT

Magnetic field sensors based on organic thin-film materials have attracted considerable interest in recent years as they can be manufactured at very low cost and on flexible substrates. However, the technological relevance of such magnetoresistive sensors is limited owing to their narrow magnetic field ranges (∼30 mT) and the continuous calibration required to compensate temperature fluctuations and material degradation. Conversely, magnetic resonance (MR)-based sensors, which utilize fundamental physical relationships for extremely precise measurements of fields, are usually large and expensive. Here we demonstrate an organic magnetic resonance-based magnetometer, employing spin-dependent electronic transitions in an organic diode, which combines the low-cost thin-film fabrication and integration properties of organic electronics with the precision of a MR-based sensor. We show that the device never requires calibration, operates over large temperature and magnetic field ranges, is robust against materials degradation and allows for absolute sensitivities of <50 nT Hz(-1/2).

8.
Phys Rev Lett ; 104(1): 017601, 2010 Jan 08.
Article in English | MEDLINE | ID: mdl-20366393

ABSTRACT

Organic semiconductors offer a unique environment to probe the hyperfine coupling of electronic spins to a nuclear spin bath. We explore the interaction of spins in electron-hole pairs in the presence of inhomogeneous hyperfine fields by monitoring the modulation of the current through an organic light emitting diode under coherent spin-resonant excitation. At weak driving fields, only one of the two spins in the pair precesses. As the driving field exceeds the difference in local hyperfine field experienced by electron and hole, both spins precess, leading to pronounced spin beating in the transient Rabi flopping of the current. We use this effect to measure the magnitude and spatial variation in hyperfine field on the scale of single carrier pairs, as required for evaluating models of organic magnetoresistance, improving organic spintronics devices, and illuminating spin decoherence mechanisms.

9.
Mol Phylogenet Evol ; 14(2): 195-217, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10679155

ABSTRACT

Phylogenetic relationships among the 22 genera of the palm subfamily Calamoideae were investigated using DNA sequence data from the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast rps16 intron. The rps16 intron displayed low levels of variation, corroborating previous reports that the chloroplast genome of palms is highly conserved. High levels of within-individual polymorphism were identified in the ITS region, indicating that concerted evolution is not effectively homogenizing the ITS repeats. In the majority of cases, multiple clones from individuals resolved as monophyletic. However, the high levels of homoplasy in the ITS dataset, along with generally poor jackknife support for many clades, led to concerns that topologies obtained from these data might be unreliable. Nevertheless, congruence between trees based on ITS data alone and those based on rps16 intron data was high. Simultaneous analyses of both datasets yielded well-resolved topologies with high levels of jackknife support. A number of exciting groups emerged from the analyses: the African rattan clade comprising the endemic African rattan genera Laccosperma, Eremospatha, and Oncocalamus; the Lepidocaryeae-Raphia clade comprising the fan-leaved New World tribe Lepidocaryeae and the African genus Raphia; and the Asian clade comprising all Asian genera except Eugeissona. The position of Eugeissona was variable, although it did not resolve inside any of the three major clades mentioned above.


Subject(s)
Chloroplasts/genetics , Phylogeny , Trees/physiology , DNA, Ribosomal/genetics , Introns , Models, Biological , Plant Proteins/genetics
10.
Mol Phylogenet Evol ; 14(2): 218-31, 2000 Feb.
Article in English | MEDLINE | ID: mdl-10679156

ABSTRACT

Phylogenetic relationships among the rattan palm genera Calamus, Daemonorops, Ceratolobus, Calospatha, Pogonotium, and Retispatha were investigated using DNA sequences from the nontranscribed spacer of 5S nrDNA. Moderate levels of intragenome polymorphism were identified, indicating that concerted evolution is not completely homogenizing the multiple copies of the 5S nrDNA repeat present in the nuclear genome. The existence of intragenome polymorphism did not excessively interfere with phylogeny reconstruction because, in the majority of cases, multiple clones obtained from individual species were resolved as monophyletic groups. The highly speciose genus Calamus was found to be nonmonophyletic with all five remaining genera being embedded within it. A number of major lineages within Calamus were resolved, one of which included the monotypic genus Calospatha, another included the monotypic genus Retispatha, and a third included a monophyletic group comprising Daemonorops, Ceratolobus, and Pogonotium. While the findings indicate that generic circumscriptions require revision, a nomenclatural solution was not sought at this stage because inadequate sampling and lack of support at basal nodes suggested that the topologies obtained might not be entirely reliable. Under these circumstances, name changes to such an important group would be both unhelpful and irresponsible.


Subject(s)
DNA, Ribosomal/genetics , Phylogeny , Trees/genetics , Africa , Evolution, Molecular , Genetic Variation , Likelihood Functions , Models, Biological , Sequence Analysis, DNA
11.
Bone Marrow Transplant ; 21(8): 775-8, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9603400

ABSTRACT

We report long-term results of high-dose cyclophosphamide, etoposide and carboplatin with ABMT in 20 patients with metastatic breast cancer. Median age of the group was 41 years, ECOG performance status = 0 in 18 patients and 1 in two patients. Twelve patients had received adjuvant chemotherapy. Predominant sites of metastases were lung (eight), chest wall (four), liver (four), bone (three) and lymph nodes (three). Response to pretransplant chemotherapy was complete (CR) in four patients, partial (PR) in 10 patients and stable (SD) in five patients. After high-dose chemotherapy eight patients were in CR, six PR, four SD and one progressive disease. Two patients died of regimen-related toxicities (candidal sepsis and alveolar hemorrhage). With a median follow-up period of 55 months (minimum 48 months), 12 patients have died of recurrent breast cancer, one died of toxicity of salvage chemotherapy, two are alive with disease, two are alive and free of progressive disease. One patient with relapsed disease was lost to follow-up. Median event-free survival is 6 months and median overall survival is 17 months. All three of the long-term disease-free survivors had predominantly nodal disease. Two of these three patients presented with metastatic disease and received high-dose chemotherapy with ABMT as part of initial therapy for breast cancer; two of three attained CR to standard-dose cytoreductive therapy; none received doxorubicin-containing adjuvant chemotherapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Breast Neoplasms/therapy , Adult , Breast Neoplasms/mortality , Carboplatin/administration & dosage , Cyclophosphamide/administration & dosage , Etoposide/administration & dosage , Humans , Middle Aged , Neoplasm Metastasis , Survival Rate , Transplantation, Autologous
12.
J Int Neuropsychol Soc ; 2(6): 477-85, 1996 Nov.
Article in English | MEDLINE | ID: mdl-9375151

ABSTRACT

Motor measures are sensitive to central lesions, but they are also affected by peripheral injury and motivation. The motor skills profiles of proven brain injury clients were compared with the profiles of healthy postconcussion patients. The chief result was a double dissociation: The traumatic brain injury (TBI) group produced a motor dysfunction gradient consistent with upper motor neuron disease, while the compensation-seeking postconcussion group produced a nonphysiologic pattern. Objective measures of behavioral pain and emotional distress did not correlate with the findings. Motor skill deficiencies in postconcussion syndrome (PCS) are probably functional in nature.


Subject(s)
Brain Concussion/diagnosis , Brain Damage, Chronic/diagnosis , Brain Injuries/diagnosis , Neuropsychological Tests , Psychomotor Disorders/diagnosis , Adult , Brain Concussion/psychology , Brain Damage, Chronic/psychology , Brain Injuries/psychology , Diagnosis, Differential , Female , Humans , Male , Malingering/diagnosis , Malingering/psychology , Middle Aged , Motor Neuron Disease/diagnosis , Motor Neuron Disease/psychology , Neurologic Examination , Psychomotor Disorders/psychology
13.
Am J Hematol ; 51(2): 137-40, 1996 Feb.
Article in English | MEDLINE | ID: mdl-8579054

ABSTRACT

Essential thrombocythemia (ET) is an uncommon myeloproliferative disorder, which is thought to develop from a multipotent stem cell. Like other myeloproliferative diseases, ET is associated with an increased risk of development of acute leukemia (AL). However, the large majority of cases of leukemic transformation in ET are thought to be related to prior therapy, usually radioactive phosphorous or alkylating chemotherapy, and the development of AL in ET is extremely rare in the untreated patient. In this report, two cases of ET which evolved into AL without prior exposure to radiation or alkylating agents, and which were treated with long-term hydroxyurea therapy, are described. The first case had cytogenetic changes in the bone marrow suggestive of therapy-associated leukemia, and the second developed myelodysplastic syndrome on therapy which was likely chemotherapy-induced and led to acute leukemia. Prolonged used of hydroxyurea in patients with ET may lead to therapy-associated acute leukemia.


Subject(s)
Antineoplastic Agents/adverse effects , Hydroxyurea/adverse effects , Leukemia, Myeloid/etiology , Thrombocythemia, Essential/drug therapy , Acute Disease , Humans , Male , Middle Aged , Thrombocythemia, Essential/pathology
14.
Breast Cancer Res Treat ; 32(1): 57-65, 1994.
Article in English | MEDLINE | ID: mdl-7819587

ABSTRACT

Flow cytometric analysis of DNA ploidy and S-phase fraction are well recognized prognostic indicators in breast cancer. The present paper deals with the widening of the applications of flow cytometry to monitoring the effectiveness of antiestrogen therapy, detecting clonal selection and emergence of drug resistance, and monitoring chemosensitizing properties of drugs. Antiestrogen activity can be studied by DNA flow cytometry to address clinical research problems such as patient-specific pharmacokinetics, dosing compliance, and acquired antiestrogen resistance. Patient plasma specimens containing various concentrations of triphenylethylenes can be monitored for drug-induced effects using cell cycle measurements and correlated to in vivo drug levels. DNA flow cytometry has also been instrumental in the study of the effects of prolonged low-dose (0.5 microM for > 100 days) tamoxifen treatment on human estrogen receptor negative MDA-MB-231 cells, where it was shown that tamoxifen may significantly alter cell cycle kinetics and tumorigenicity of these cells, selecting a new, more aggressive, and rapidly growing clone. Lastly, it has been shown that the chemosensitizing properties of another triphenylethylene antiestrogen, toremifene, on estrogen receptor negative, multidrug resistant MDA-MB-231-A1 human breast cancer cells can be studied using flow cytometric analysis. Toremifene (and its metabolites N-desmethyltoremifene and toremifene IV) are able to "resensitize" MDA-MB-231-A1 cells to vinblastine and doxorubicin, as reflected in a marked shift of cells to G2/M phase of the cell cycle. Flow cytometry is a widely available technique that might be applied clinically to monitor, at the cellular level, drug effects on tumors, including the modulators of drug resistance.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , DNA, Neoplasm/analysis , Flow Cytometry , Antineoplastic Agents/therapeutic use , Cell Cycle/drug effects , Drug Resistance, Multiple , Estrogen Antagonists/therapeutic use , Humans
15.
Med Pediatr Oncol ; 22(6): 384-8, 1994.
Article in English | MEDLINE | ID: mdl-8152399

ABSTRACT

There is a well described association between multicentric angiofollicular hyperplasia and non-Hodgkin's lymphoma and/or Kaposi's sarcoma. Two cases of multifocal angiofollicular hyperplasia and associated carcinomas and non-Hodgkin's lymphoma are reported. We suggest that underlying immunological defects in patients with multicentric angiofollicular hyperplasia make them susceptible to the development of carcinomas, as well as non-Hodgkin's lymphoma and Kaposi's sarcoma.


Subject(s)
Adenocarcinoma/etiology , Carcinoma, Renal Cell/etiology , Castleman Disease/complications , Kidney Neoplasms/etiology , Lymphoma, Large B-Cell, Diffuse/etiology , Prostatic Neoplasms/etiology , Aged , Humans , Male , Middle Aged
17.
Bone Marrow Transplant ; 12(3): 301-3, 1993 Sep.
Article in English | MEDLINE | ID: mdl-8241990

ABSTRACT

Autologous BMT performed in a 57-year-old woman with relapsed large cell lymphoma was complicated by two consecutive episodes of diffuse alveolar hemorrhage (DAH). The second episode occurred immediately after infusion of autologous BM. DAH is an increasingly recognized complication of autologous BMT and carries a high mortality. It is characterized by dyspnea, cough, bilateral pulmonary infiltrates and progressively bloodier aliquots of bronchoalveolar lavage fluid. The pathogenesis is probably multifactorial involving an initial insult to lung endothelium with inflammatory cells serving as the mediators of subsequent injury. The rapid development of DAH following marrow infusion strongly implicates DMSO as a potential cause in our patient.


Subject(s)
Bone Marrow Transplantation/adverse effects , Hemorrhage/etiology , Lung Diseases/etiology , Lymphoma, Large B-Cell, Diffuse/surgery , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Combined Modality Therapy , Cryopreservation , Dimethyl Sulfoxide/adverse effects , Dyspnea/etiology , Fatal Outcome , Female , Hemorrhage/pathology , Humans , Hypoxia/etiology , Lung Diseases/pathology , Lymphoma, Large B-Cell, Diffuse/drug therapy , Middle Aged , Pulmonary Alveoli/pathology , Thrombocytopenia/therapy , Tissue Preservation , Transplantation, Autologous/adverse effects
18.
Cutis ; 52(2): 89-90, 1993 Aug.
Article in English | MEDLINE | ID: mdl-8404022

ABSTRACT

A nineteen-year-old woman whose Hodgkin's disease had relapsed experienced acral erythema in association with a asymptomatic pericardial friction rub following autologous bone marrow transplantation. An echocardiogram revealed a large pericardial and right pleural effusion. Since blood cultures gave negative results, renal function was normal, and the patient had neither neutropenia nor elevated temperature, an infectious cause was deemed unlikely and invasive procedures were not performed. These effusions resolved spontaneously. We propose that this patient's acral erythema and associated pericardial and pleural inflammation represent cutaneous and serosal toxic reactions to high-dosage chemotherapy that occur with the onset of leukocyte recovery. If so, acral erythema may signal the beginning of a toxic drug reaction. The appearance of erythema associated with lymphocyte recovery is due to immune hypersensitivity secondary to immaturity of the reconstituting immune system. Thus, we recommend that patients with acral erythema be examined for pleuropericarditis, especially if they experience chest pain.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cyclophosphamide/adverse effects , Erythema/chemically induced , Etoposide/adverse effects , Hand Dermatoses/chemically induced , Pericarditis/chemically induced , Adult , Bone Marrow Transplantation , Chest Pain/chemically induced , Cyclophosphamide/administration & dosage , Edema/chemically induced , Etoposide/administration & dosage , Female , Hodgkin Disease/drug therapy , Hodgkin Disease/radiotherapy , Hodgkin Disease/surgery , Humans , Joint Diseases/chemically induced , Pleurisy/chemically induced , Syndrome , Whole-Body Irradiation
19.
Oncol Res ; 5(12): 461-6, 1993.
Article in English | MEDLINE | ID: mdl-8086667

ABSTRACT

The in vivo growth rate and the chemosensitivity patterns of a cell clone selected by tamoxifen from the estrogen receptor-negative human breast cancer cell line MDA-MB-231 was studied in the nude mouse model and with flow cytometry. To investigate the growth rate of the wild-type and clone cells in vivo, the cells were inoculated into the opposite flanks of 5 male nude mice. Drug sensitivity to doxorubicin (10 ng/mL), vinblastine (1 ng/mL), and paclitaxel (1 ng/mL) was examined in wild-type/clone cell mixture using flow cytometry. Northern blot technique was used to study the expression of mdr-1 messenger RNA in both the wild-type and the clone cells. The tumors derived from the clone and wild-type cells were, following a 3-week growth period, 260.2 +/- 78.8 mm2 vs. 68.3 +/- 50.8 mm2 in size, respectively (P < 0.001). Following a 28-day continuous exposure, doxorubicin was selectively, toxic to the wild-type cells, while having no apparent effect on the clone population. However, paclitaxel- and vinblastine-treated wild-type/clone cell mixtures did not exhibit a differential cytotoxic effect on either cell population. It was concluded that the clone selected by tamoxifen shows an aggressive growth rate in vivo and an altered chemosensitivity pattern to doxorubicin in vitro.


Subject(s)
Breast Neoplasms/pathology , Doxorubicin/pharmacology , Tamoxifen/pharmacology , Animals , Cell Division/drug effects , Drug Resistance , Female , Humans , Male , Mice , Mice, Inbred BALB C , Tumor Cells, Cultured
20.
Oncol Res ; 5(6-7): 207-12, 1993.
Article in English | MEDLINE | ID: mdl-8123940

ABSTRACT

The clinical study of compounds that modulate multidrug resistance has been hindered by both the toxicities of these agents and the inability to monitor their effectiveness at the level of the tumor cell. Previously, toremifene has been shown to be well tolerated clinically and to sensitize multidrug resistant cells to the effects of cytotoxic chemotherapeutic agents. The chemosensitizing properties of toremifene in estrogen receptor negative, multidrug resistant MDA-MB-A1 human breast cancer cells were studied using flow cytometric analysis and growth inhibition assays. Cell cycle kinetics of MDA-MB-A1 cells were not significantly affected by treatment with either toremifene, N-desmethyltoremifene, Toremifene IV or vinblastine alone, as the majority of cells remained in G0/G1. However, preincubation with toremifene or one of its metabolites for 72 hours followed by treatment for one hour with vinblastine caused a marked shift of cells to G2/M, as cells appeared to be blocked in that phase of the cell cycle. This result was nearly identical to the effect of vinblastine alone on vinblastine-sensitive MDA-MB-231 breast cancer cells and can be interpreted as a "resensitization" by toremifene of MDA-MB-A1 cells to vinblastine. This chemosensitizing effect of toremifene was accompanied by an enhanced inhibition of cell growth by vinblastine. The chemosensitizing effects of toremifene or one of its metabolites in combination with cytotoxic chemotherapy can be effectively monitored by flow cytometry, an easily accessible technique.


Subject(s)
Breast Neoplasms/pathology , Drug Resistance , Toremifene/pharmacology , Vinblastine/pharmacology , Breast Neoplasms/drug therapy , Cell Cycle/drug effects , Cell Division/drug effects , Drug Synergism , Female , Flow Cytometry , Humans , Tumor Cells, Cultured
SELECTION OF CITATIONS
SEARCH DETAIL
...