Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This paper describes tubulointerstitial changes of the kidney in association with a) pathophysiology of paraproteinuria and related disorders, and b) the management of leukemia and malignant lymphoma. Various forms of tubulointerstitial changes might be provoked following the accumulation of "abnormal macromolecules" In a), multiple myeloma, light chain cast nephropathy (myeloma kidney), AL amyloidosis, light chain deposition disease, macroglobulinemia, cryoglobulinemia etc. are briefly reviewed. In the majority of cases, leukemia and lymphoma do not manifest themselves as tubulointerstitial disorders. However, a large number of patients suffer from tubulointerstitial abnormalities in the course of and/or after receiving chemotherapy. Thus it is explained, in b), why treatment for hematological malignancy is apt to induce tubulointerstitial complications. In this context, drugs responsible for the development of tubulitis and/or interstitial fibrosis are briefly reviewed.
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PMID:[Tubulointerstitial changes in some hematological disorders]. 756 42

The huge discrepancies in the proportion of tumors positive for P-gp observed in the literature limit any definite conclusions, except for the urgent need for standardized methods to compare results. It is well known by scientists that only positive results are published. For this reason, the frequency of P-gp expression in leukemia and lymphoma may be overestimated. The role of the MDR phenotype in clinical resistance is also not clearly demonstrated, because of the frequent association of other markers of bad prognosis on the same subset of cells (CD34, CD7 in leukemia). Hematologic malignancies are the most extensively studied tumors for drug resistance, and they could be a model for the therapeutic use of modifier agents. Many clinical trials are now ongoing in myeloma, acute leukemia, and lymphoma, with new modifier agents. The standardization of methods for P-gp, permitting large multicentric studies, and the results of randomized studies with modifier agents will help us know if mdr1 gene overexpression is of clinical importance in hematologic malignancies.
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PMID:P-glycoprotein in adult hematologic malignancies. 764 63

Interleukin-4 (IL-4), originally identified as a B-cell growth factor, has been shown to inhibit certain stages of hematopoietic stem cells. Recently, IL-4 has been recognized as a negative regulatory factor in the growth of hematologic malignancy. In myeloid leukemias, IL-4 can suppress the growth of growth factor-dependent leukemic blast cells derived from acute myelogenous leukemia (AML). IL-4 also suppresses the growth of chronic myelomonocytic leukemia cells through inhibiting the "autocrine" production of IL-6 or granulocyte/macrophage colony-stimulating factor. In lymphoid malignancies, IL-4 can inhibit the proliferation of neoplastic cells from Ph1-positive acute lymphoblastic leukemia, non-Hodgkin's B-cell lymphoma, and multiple myeloma. Thus, IL-4 is expected to be useful as a therapeutic agent for these hematologic malignancies.
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PMID:The role of interleukin-4 in the negative regulation of leukemia cell growth. 768 64

The widespread use of alpha-interferon (IFN-alpha) therapy in different diseases draws attention to its side effects, such as autoimmune-related diseases, especially thyroid autoimmune dysfunctions. Data about hepatitis and nonhematologic neoplasia are available, while data about hematologic malignancies are fragmentary. We studied the incidence of autoimmune-related disturbances and thyroid dysfunctions in 54 consecutive patients suffering from hematologic malignancies, treated with recombinant human IFN-alpha for a mean time of 15.9 +/- 8.9 months. Our results minimize the incidence of autoimmune dysfunctions in hematologic malignancies as side effects of IFN-alpha therapy. We registered the appearance of autoantibodies in only 3 females (5% of total): 2 patients (1 affected with essential thrombocythemia and one with multiple myeloma) presented antithyroglobulin antibodies with no clinical symptoms; 1 patient, affected with essential thrombocythemia, developed antinuclear antibodies with arthralgia and myalgia. ARA criteria for systemic lupus erythematosus were not fulfilled but the therapy had to be interrupted. No patient developed thyroid dysfunction. In patients with hematologic malignancies, the dosage and the duration of IFN-alpha treatment do not seem to influence the appearance of autoantibodies, while female sex appears to be a risk factor.
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PMID:Autoimmune thyroid dysfunctions in hematologic malignancies treated with alpha-interferon. 772 47

10 patients were subjected to tandem transplantation for breast cancer (n = 3), ovarian cancer (n = 2) and multiple myeloma (n = 5), at the Second Department of Medicine, Donauspital, Vienna. The breast cancer patients were in stages 2 and 3, respectively, at diagnosis and entered complete remission thereafter. 2 of them developed lymph node metastasis and additional local recurrence, the 3rd patient presented with distant metastasis. The 2 patients with ovarian cancer were in stages Figo III and IV, respectively, at the time of diagnosis, and showed minimal residual disease at second-look-operation. 5 patients with multiple myeloma were in stage 3 pretransplant. Peripheral stem cells were obtained after either high-dose cyclophosphamide or FEC induction and application of cytokines. In 4 patients, tandem transplantation has been completed. 1 patient with multiple myeloma, who had received total body irradiation in combination with chemotherapy for the 2nd transplant, succumbed from idiopathic interstitial pneumonia. No severe clinical complications were observed in all other patients. All patients with solid tumors entered complete remission after the 1st transplantation. 3 of them completed tandem transplantation. Of these, 2 remain in continuous complete remission, the 3rd patient relapsed in lymph nodes day 485. In patients who received only 1 course of high dose chemotherapy with stem cell transplantation, relapses occurred on days 29 and 75, respectively. All patients with multiple myeloma entered only partial remission. We conclude that supralethal chemotherapy with peripheral blood stem cell support is a safe procedure that may at least induce prolonged remissions in solid tumors and hematologic malignancies.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Tandem transplantation with peripheral autologous hematopoietic blood stem cells in treatment of oncologic and hematologic malignancies. Initial results of the Donauspital, Vienna]. 776 51

Hepsulfam is a bisulfamic ester which is similar in structure to busulfan and is believed to act as a bifunctional alkylator inducing both DNA-DNA and DNA-protein crosslinks. Prior studies in patients with refractory solid tumors have identified the dose-limiting toxicity of hepsulfam to be cumulative myelosuppression resulting in prolonged leukopenia and thrombocytopenia. This phase I trial was designed to determine the maximally tolerated dose of hepsulfam administered intravenously in patients with refractory leukemias and other advanced hematologic malignancies. Hepsulfam was administered as a 30-min or 2-h intravenous infusion to 21 patients with advanced leukemia or multiple myeloma. All patients had been extensively treated and had progressive disease. Cycles were repeated every 5 weeks. Cohorts of patients were treated at 360, 480, 640, and 800 mg/m2. The dose-limiting toxicity of intravenous hepsulfam was severe encephalopathy. The single patient treated at 800 mg/m2 became comatose within 48 h and required 3 weeks for his mental status to return to baseline. There were, however, no irreversible neurological sequelae. Several patients treated at 640 mg/m2 had clinical evidence of toxic deliriums and slowing of alpha rhythm waves on electroencephalograms indicative of a gray-matter encephalopathy. When hepsulfam was infused over 30 min, patients complained of uncomfortable parasthesias, but when the drug was administered over 2 h, these acute symptoms were less common. Myelosuppression was observed in most patients. Among those patients who had some suppression of their leukemia, peripheral blood counts recovered to pretreatment levels after 3-5 weeks. Apart from CNS toxicity, non-hematologic toxicity was minimal. Pharmacokinetic studies demonstrated rapid clearance of hepsulfam so that the drug was not reliably detected in the plasma after 24 h. The recommended phase II dose of hepsulfam as a single 2-h intravenous infusion is 480 mg/m2, but this dose provided relatively little clinical benefit for patients with refractory leukemia. The dose-limiting toxicity is CNS toxicity with increasingly severe encephalopathy at doses > or = 640 mg/m2. It would be reasonable to investigate further dose escalation of hepsulfam in a divided dose schedule to minimize the peak concentrations which may be related to the encephalopathy. EEG monitoring is recommended for early detection of slowing of alpha rhythm waves. Hematopoietic stem cell support will probably be required at total doses exceeding 800 mg/m2.
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PMID:Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies. 778 Nov 39

An 83-year-old black woman with previously diagnosed essential thrombocythemia was treated with thiotepa to control the excessive number of platelets. Approximately 10 years later, multiple myeloma developed. This appears to be the first case of multiple myeloma occurring after alkylating agent therapy for essential thrombocythemia. Although the mechanism of the development of multiple myeloma has yet to be defined, continuing progress in cell biology may prove a strong association between multiple myeloma and other hematologic malignancies.
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PMID:Multiple myeloma after treatment of essential thrombocythemia. 781 32

Hypercalcemia may be a manifestation of a variety of disorders including hyperparathyroidism, hypervitaminosis D, sarcoidosis, multiple myeloma, hyperthyroidism, acute osteoporosis, metastatic bone disease, and a number of primary malignancies. Hypercalcemia may be seen in as many as 1.5% of all patients with malignant disease, with or without bony metastases. The neoplasms most commonly associated with hypercalcemia include carcinoma of the lung (all cell types), breast cancer, squamous cell carcinomas, hematologic malignancies, and renal cell carcinoma. Observation of a number of instances of hypercalcemia attendant on urologic malignancies prompts the brief report of 4 characteristic cases with documentation of response to therapy. Management of severe and debilitating hypercalcemia is emphasized. Urologists should be aware of new agents available for such treatment.
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PMID:Hypercalcemia and urologic malignancies. 781 68

The p16 protein is a cyclin inhibitor encoded by a gene located in 9p21, which may have antioncogenic properties, and is inactivated by homozygous p16 gene deletion or, less often, point mutation in several types of solid tumors often associated to cytogenetic evidence of 9p21 deletion. We looked for homozygous deletion and point mutation of the p16 gene in acute lymphoblastic leukemia (ALL), where 9p21 deletion or rearrangement are also nonrandom cytogenetic findings. Other hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), and myeloma were also studied. Homozygous deletion of the p16 gene was seen in 9 of the 63 (14%) ALL analyzed, including 6/39 precursor B-ALL, 3/12 T-ALL, and 0/12 Burkitt's ALL. Three of the 7 ALL with 9p rearrangement (including 3 of the 5 patients where this rearrangement was clearly associated to 9p21 monosomy) had homozygous deletion compared to 5 of the 55 patients with normal 9p (the last patient with homozygous deletion was not successfully karyotyped). Single stranded conformation polymorphism analysis of exons 1 and 2 of the p16 gene was performed in 88 cases of ALL, including the 63 patients analyzed by Southern blot. Twenty-six of the cases had 9p rearrangement, associated to 9p21 monosomy in at least 12 cases. A missense point mutation, at codon 49 (nucleotide 164), was seen in only 1 of the 88 patients. No homozygous deletion and no point mutation of the p16 gene was seen in AML, MDS, CLL, and myeloma. Homozygous deletion of interferon alpha genes (situated close to p16 gene in 9p21) was seen in only 3 of the 9 ALL patients with p16 gene homozygous deletion, and none of the ALL without p16 gene homozygous deletion. Our findings suggest that homozygous deletion of the p16 gene is seen in about 15% of ALL cases, is not restricted to cases with cytogenetically detectable 9p deletion, and could have a pathogenetic role in this malignancy. On the other hand, p16 point mutations are very rare in ALL, and we found no p16 homozygous deletions or mutations in the other hematologic malignancies studied.
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PMID:p16 gene homozygous deletions in acute lymphoblastic leukemia. 783 69

Glucocorticoids are highly effective in inducing the cytolysis of cells of lymphocytic origin. This property has resulted in their incorporation into chemotherapy regimens used in the treatment of hematologic malignancies. Studies at the molecular and cellular levels have demonstrated that the hormone-induced cytolytic response is mediated through a highly specific cytoplasmic glucocorticoid receptor (GR). The GR has been cloned and sequenced and found to be organized into a discrete series of domains which mediate the receptor functions of hormone binding, nuclear translocation, DNA binding and transcriptional modulation. Thus, the binding of glucocorticoids by the GR induces a series of cellular events which result in the activation or repression of a network of glucocorticoid responsive genes and produces a specific cellular response. Prolonged exposure to glucocorticoids ultimately causes resistance to develop; thereby limiting the usefulness of this class of drugs. Studies addressing the mechanism of resistance have shown that the GR is the primary target of genetic alterations that lead to resistance to cytolysis. Using mouse and human cell lines as model systems, it has been shown that the vast majority of glucocorticoid resistant mutants express low levels or altered forms of the GR. Similarly, in vivo studies on patients have suggested that low GR levels are associated with a poor response to glucocorticoid based therapies. Recently, aberrant GR isolated from a patient with multiple myeloma resistant to glucocorticoids were found to harbor deletions in their hormone binding domains. Sequencing of the receptors suggested that each arose as a result of alternate splicing events. In both cases, the latter event produces a receptor unable to bind hormone leading to the speculation that alternate splicing may serve as a mechanism by which a cell evades the effects of glucocorticoids. The therapeutic implications for patients expressing aberrant receptors is discussed.
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PMID:Glucocorticoid receptors and resistance to glucocorticoids in hematologic malignancies. 787 93


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