Treatment of cutaneous T cell lymphoma.
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Biomedical subjects
Publications and source records attributed to R L Edelson.
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Biotinylated psoralen (BPsor), a psoralen derivative containing a biotin moiety attached via a long-chain, positively charged linker, has been synthesized and its interactions with DNA and avidin have been studied. As do other psoralen derivatives, BPsor photoreacts with DNA to form interstrand crosslinks. The biotin binds to streptavidin after the reaction of BPsor with DNA, and this property has been used to measure low levels of BPsor modified DNA by ELISA with streptavidin and biotinylated alkaline phosphatase. In addition, BPsor retains the biological activity of psoralen, as shown by its ability to inhibit lymphocyte proliferation at a level of 10 ng/ml.
The antitumor antibiotic gilvocarcin (GV) when photoactivated with UV radiation induced single strand breaks in superhelical pBR322 DNA. The optimal wavelengths for nicking DNA correlated with the absorbance maximum of GV near the visible region (398 nm). The response of lymphocytes to stimulation by phytohemagglutinin was reduced to 10% of controls at 0.10 ng/ml GV in combination with 3 J/cm2 of ultraviolet A (UVA) radiation. The potency of gilvocarcin is attributed to two factors: its strong tendency to intercalate with DNA (K = 6.6 X 10(5) M-1) and its intense absorption of UVA radiation (E398 = 11971 M-1 cm-1).
A new method has been developed to extract 8-methoxypsoralen (8-MOP) from human plasma and to prepare samples for high performance liquid chromatography (HPLC) analysis. Plasma samples are passed through solid phase extraction cartridges that are essentially HPLC "microcolumns" consisting of a bonded silica sorbent that, after activation, selectively retain 8-MOP and then release it when exposed to an eluting solvent. The 8-MOP collected from the cartridge is analyzed by reversed phase HPLC. With this new technique, the 8-MOP is completely recovered and as little as 10 ng/ml can be detected in a 1-ml plasma sample. The average plasma level in a series of 17 patients who had ingested Oxsoralen (approximately 0.6 mg/kg) was 117 ng/ml (+/- 79).
Genomic DNA digests of peripheral blood lymphocytes from 13 patients with the leukemic phase of the T cell neoplasm cutaneous T cell lymphoma were studied by hydridization using probes for the constant region of the beta chain of the T cell receptor, the joining region of the immunoglobulin heavy chain gene, and the kappa and lambda light chain genes. Lymphocytes from all 13 cutaneous T cell lymphoma patients contained DNA with clonal rearrangements of the beta chain gene of the T cell receptor. In addition, DNA from 4 patients contained an immunoglobulin gene rearrangement. T cell enrichment studies of peripheral blood lymphocytes from 2 patients confirmed that the immunoglobulin gene joining region rearrangement was confined to the T cell population. These results demonstrate that cutaneous T cell lymphoma is a clonal T cell malignancy that frequently expresses a dual genotype. A multiparameter approach, including DNA probes for the beta chain of the T cell receptor, as well as the immunoglobulin genes, immunophenotyping, and cytogenetics, is valuable in the diagnosis of cutaneous T cell lymphoma.
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Photopheresis is a relatively safe and technically simple modality for immunomodulation. The extracorporeal activation of a drug with UVA constitutes a novel form of drug delivery. The usefulness of this system in erythrodermic CTCL is well established. Immunomodulating therapy can thus be conducted outside the host, where controlled conditions permit cellular manipulations not possible in the intact patient. This system is an excellent paradigm for future immunomodulating therapies in diseases such as pemphigus vulgaris and lupus erythematosus.
Chromosome analysis from stimulated and unstimulated lymphocytes of blood, skin, and lymph nodes demonstrated a clonal chromosomal abnormality in eight of 46 patients with cutaneous T-cell lymphoma (CTCL). Nonclonal abnormalities were found in nine other patients. Unstimulated lymph node cultures identified the highest proportion of clonal changes. Clonal changes were found most often in patients with advanced disease, and in patients who tested positive with a monoclonal antibody previously shown to detect the T-cells involved in CTCL. Analysis of the eight abnormal clones and seven others found before or since this consecutive series showed that identifiable changes involving the known sites of T-cell receptor genes on chromosomes #7 and #14 were not usually present. An association between CTCL and chromosome rearrangements of chromosome #10 is suggested both from our cases and those found in the literature. This observation is of interest because this chromosome contains the gene for the interleukin-2 receptor.
A woman who emigrated to the United States from the Dominican Republic developed the first signs of cutaneous T cell lymphoma during the last trimester of her pregnancy. This patient, found to have a positive reaction against human T-lymphotropic (leukemia-lymphoma) virus type I (HTLV-I), was followed up prospectively from the appearance of the initial skin lesion to the development of high-count helper T cell leukemia. Antibodies reactive with the core protein of HTLV-I were also identified in her husband and mother but not in her 2-year-old daughter. Examination of the patient's course provides clues about the latency period and transmission of HTLV-I and highlights similarities between HTLV-I-positive and HTLV-I-negative cutaneous T cell lymphoma.
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4'-Aminomethyl-4,5',8-trimethylpsoralen has been chemically conjugated to insulin using a carbodiimide derivative. The psoralen moiety retains its photochemical reactivity as evidenced by its ability to crosslink DNA after exposure to long wavelength ultraviolet light (UVA, 320-400 nm). This chimeric molecule has been used to selectively kill a population of lymphocytes whose expression of insulin receptors has been stimulated with phytohemagglutinin. Insulin carries the psoralen into the cell via receptor-mediated endocytosis, where it is subsequently activated by exposure to UVA light. The UVA induced activity of AMT-insulin can be blocked by the presence of native insulin. The viability of unstimulated lymphocytes was not affected by AMT-insulin and UVA light. The hybrid insulin-psoralen molecule may be a prototype for a family of phototoxic drugs which can be selectively delivered to subsets of lymphocytes.
Cutaneous T cell lymphoma is a malignancy of helper T cells, which have a propensity to infiltrate the skin. The incidence of the disease appears to exceed that of Hodgkin's disease, making it the most common lymphoma of adults. Advances in our knowledge of the biology of the malignant T cells should facilitate new and more effective forms of treatment.