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)

Spleen cells from a mouse and a rat immunized with vinblastine coupled to bovine serum albumin were fused in two independent experiments with P3 X 63-Ag8 (non-secreting variant) mouse myeloma cells. Three mouse X mouse (Vinca 1-3) and two rat X mouse (Vinca 4 and 5) hybrids were selected for production of Vinca alkaloid binding monoclonal antibodies. Each antibody had characteristic cross-reactivities with alkaloids structurally related to vinblastine: Vinca 1 reacted preferentially with deacetylated alkaloids (deacetyl vinblastine and vindesine) and Vinca 2 had a higher affinity for vinblastine and vincristine. Vinca 3-5 recognized equally vinblastine, vincristine and vindesine but differed with respect to their affinities for other analogues. No significant cross-reactivity of the monomeric alkaloids vindoline or catharanthine was observed with any antibody, and dimeric alkaloids modified in the catharanthine moiety had reduced immunoreactivity. Mouse monoclonal antibodies (Vinca 1 and 3) showed moderate affinity (2.2 X 10(-7) and 5.8 X 10(-9) M) for their respective best ligands and fast kinetics (dissociation rate constants greater than 3 X 10(-3) sec-1). Vinca 4 and 5, derived from the rat X mouse hybrids, had much higher affinities (1.5 X 10(-11) and 1.1 X 10(-11) M) and slower kinetics (dissociation rate constants: 2.4 X 10(-5) and 7.2 X 10(-6) sec-1). The major difference between these two antibodies was that Vinca 4 binds and releases the antigen more rapidly than Vinca 5 does. Somatic hybridization techniques thus generated monoclonal antibodies recognizing a given class of low mol. wt antigens with variable specificity, affinity and kinetic behavior, allowing the selection of reagents most appropriate for particular immunochemical applications.
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PMID:Monoclonal antibodies to antitumor Vinca alkaloids: thermodynamics and kinetics. 400 Jan 31

Prognostic factors in 68 consecutive patients with myeloma treated at the National Cancer Center Hospital from 1962 to 1984 were analyzed. Median survival time from onset was 100 months for stage I, 72 months for stage II, and 26 months for stage III of the Durie and Salmon's clinical staging system. It was 55 months in patients with normal renal function and 18 months in those with abnormal renal function. All early deaths occurred in patients with stage III disease. Hemoglobin level, bone lytic lesions and presence of Bence Jones protein were also significant prognostic factors. On the other hand, heavy chain as well as light chain subtypes of monoclonal immunoglobulin (M-component) and M-component production rate did not influence the survival of myeloma patients. The analysis of chemotherapeutic responses and survival curves according to the chemotherapy used in this study (alkylating agent vs Vinca-alkaloid plus alkylating agent) did not disclose any significant difference between the two groups. The overall response rate was 67%. The survival time from the initial chemotherapy of responding patients was significantly longer than that of nonresponders.
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PMID:Prognostic factors and therapeutic results in multiple myeloma. 405 32

The emergence of drug resistant cells is one of the main obstacles for successful chemotherapeutic treatment of haematological malignancies. Most patients initially respond to chemotherapy at the time of first clinical admission, but often relapse and become refractory to further treatment not only to the drugs used in the first treatment but also to a variety of other drugs. Laboratory investigations have now provided a cellular basis for this clinical observation of multidrug resistance (MDR). Expression of a glycoprotein (referred to as P-glycoprotein) in the membrane of cells made resistant in vitro to naturally occurring anticancer agents like anthracyclines, Vinca alkaloids and epipodophyllotoxins, has been shown to be responsible for the so-called classical MDR phenotype. P-glycoprotein functions as an ATP-dependent, unidirectional drug efflux pump with a broad substrate specificity, that effectively maintains the intracellular cytotoxic drug concentrations under a non-cytotoxic threshold value. Extensive clinical studies have shown that P-glycoprotein is expressed on virtually all types of haematological malignancies, including acute and chronic leukaemias, multiple myelomas and malignant lymphomas. Since in model systems for P-glycoprotein-mediated MDR, drug resistance may be circumvented by the addition of non-cytotoxic agents that can inhibit the outward drug pump, clinical trials have been initiated to determine if such an approach will be feasible in a clinical situation. Preliminary results suggest that some haematological malignancies, among which are acute myelocytic leukaemia, multiple myeloma and non-Hodgkin's lymphoma, might benefit from the simultaneous administration of cytotoxic drugs and P-glycoprotein inhibitors. However, randomised clinical trials are needed to evaluate the use of such resistance modifiers in the clinic.
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PMID:Multidrug resistance (MDR) genes in haematological malignancies. 776 26

The occurrence of multidrug resistance (MDR) is one of the main obstacles in the successful chemotherapeutic treatment of cancer. MDR cell lines are resistant to the so-called naturally occurring anti-cancer drugs, such as anthracyclines, Vinca alkaloids and epipodophyllotoxins, but are not cross-resistant to alkylating agents, antimetabolites and cisplatin. So far, three separate forms of MDR have been characterized in more detail: classical MDR, non-Pgp MDR and atypical MDR. Although all three MDR phenotypes have much in common with respect to cross-resistance patterns, the underlying mechanisms certainly differ. Atypical MDR is associated with quantitative and qualitative alterations in topoisomerase II alpha, a nuclear enzyme that actively participates in the lethal action of cytotoxic drugs. Atypical MDR cells do not overexpress P-glycoprotein, and are unaltered in their ability to accumulate drugs. In this review we will focus on classical and non-Pgp MDR. The molecular mechanism of classical and non-Pgp MDR is transcriptional activation of membrane-bound transport proteins. These transport proteins belong to the ATP-binding cassette (ABC) superfamily of transport systems. The classical MDR phenotype is characterized by a reduced ability to accumulate drugs, due to activity of an energy-dependent uni-directional, membrane-bound, drug-efflux pump with broad substrate specificity. The classical MDR drug pump is composed of a transmembrane glycoprotein (P-glyco-protein-Pgp) with a molecular weight of 170 kD, and is, in man, encoded by the so-called multidrug resistance (MDR1) gene. Typically, non-Pgp MDR has no P-gly-coprotein expression, yet has about the same cross-resistance pattern as classical MDR. This non-Pgp MDR phenotype is caused by overexpression of the multidrug resistance-associated protein (MRP) gene, which encodes a 190 kD membrane-bound glycoprotein (MRP). MRP probably works by direct extrusion of cytotoxic drugs from the cell and/or by mediating sequestration of the drugs into intracellular compartments, both leading to a reduction in effective intracellular drug concentrations. For the classical MDR phenotype, evidence is accumulating that it plays a role indeed, in clinical drug resistance, especially in some hematological malignancies (acute myeloid leukemia, multiple myeloma and non-Hodgkin's lymphoma) and solid tumors (soft tissue sarcomas and neuroblastoma). The association of MRP with clinical drug resistance has not been elaborated, yet, and studies on MRP expression in human cancer have just begun. We found that overexpression of MRP, as determined by RNase protection assay as well as by immunohistochemistry, occurs in several human cancers, among which are cancer of the lung, esophagus, breast and ovary, and leukemias. Further studies are indicated to establish whether elevated MRP expression at diagnosis is an unfavorable prognostic factor for clinical outcome of chemotherapy.
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PMID:Molecular mechanisms of multidrug resistance in cancer chemotherapy. 888 Aug 78

Peripheral neuropathy is one of the most important complications of multiple myeloma treatment. Neurological damage can be observed at the onset of the disease, due to the effect of monoclonal protein or radicular compression, but more often is treatment related. Vinca alkaloids in the past era, and more recently, thalidomide and bortezomib are mainly responsible. Degeneration of dorsal root ganglion is common, prevalently related to angiogenesis inhibition and cytokine modulation in the case of thalidomide and inhibition of the ubiquitin proteasome system in the case of bortezomib. Sensory neuropathy and neuropathic pain are more common; motor neuropathy and autonomic damage are less frequently observed. Neurotoxicity often affects patient's quality of life and requires dose modification or withdrawal of therapy, with a possible effect on the overall response. A prompt recognition of predisposing factors (such as diabetes mellitus, alcohol abuse, vitamin deficiencies, or viral infections) and appearance of signs and symptoms, through a periodic neurological assessment with appropriate scales, is extremely important. Effective management of treatment at the emergence of peripheral neuropathy can minimize the incidence and severity of this complication and preserve therapeutic efficacy. Dose adjustment could be necessary during treatment; moreover, gabapentin or pregabalin, tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, carbamazepine, and opioid-type analgesics are suggested according to the pain severity. Some authors reported that patients who develop peripheral neuropathy during their multiple myeloma treatments presented a particular gene expression profile; therefore, future studies could be helpful for a better understanding of possible biological pathways underlying neurotoxicity.
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PMID:Managing treatment-related peripheral neuropathy in patients with multiple myeloma. 3136 79

Vinca alkaloids, thalidomide, and eribulin are widely used to treat patients with childhood acute lymphoblastic leukemia (ALL), adults affected by multiple myeloma and locally invasive or metastatic breast cancer, respectively. However, soon after their introduction into clinical practice, chemotherapy-induced peripheral neurotoxicity (CIPN) emerged as their main non-hematological and among dose-limiting adverse events. It is generally perceived that vinca alkaloids and the antiangiogenic agent thalidomide are more neurotoxic, compared to eribulin. The exposure to these chemotherapeutic agents is associated with an axonal, length-dependent, sensory polyneuropathy of mild to moderate severity, whereas it is considered that the peripheral nerve damage, unless severe, usually resolves soon after treatment discontinuation. Advanced age, high initial and prolonged dosing, coadministration of other neurotoxic chemotherapeutic agents and pre-existing neuropathy are the common risk factors. Pharmacogenetic biomarkers might be used to define patients at increased susceptibility of CIPN. Currently, there is no established therapy for CIPN prevention or treatment; symptomatic treatment for neuropathic pain and dose reduction or withdrawal in severe cases is considered, at the cost of reduced cancer therapeutic efficacy. This review critically examines the pathogenesis, epidemiology, risk factors (both clinical and pharmacogenetic), clinical phenotype and management of CIPN as a result of exposure to vinca alkaloids, thalidomide and its analogue lenalidomide as also eribulin.
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PMID:Vinca alkaloids, thalidomide and eribulin-induced peripheral neurotoxicity: From pathogenesis to treatment. 3164 52