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)

Based on remarkable activity in refractory lymphomas, a combination of etoposide, cisplatin (both administered by 4-day continuous infusions), cytarabine (Ara-C), and dexamethasone (EDAP) was evaluated in 20 patients with advanced myeloma refractory to standard melphalan and prednisone (MP) and/or vincristine, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and dexamethasone (VAD) and even to high doses of melphalan (HDM) (seven patients). Forty percent of patients responded regardless of previously recognized risk factors (eg, duration of drug resistance, tumor mass, and serum lactic dehydrogenase [LDH] level). While the median survival was only 4.5 months, patients with good performance (Zubrod less than 2) and low or intermediate tumor stage survived more than 14 months compared with only 2 months for the remaining group. EDAP could be readily administered in the outpatient clinic, but neutropenic fever prompted hospital admission in 80% of patients, half of whom developed penumonia and sepsis, a fatal outcome in four patients. Severe myelosuppression was of short duration, so that subsequent cycles could be administered every 3 to 4 weeks. No serious extramedullary toxicity, including renal toxicity, was encountered. Marrow toxicity and hence infectious complications may be reduced by elimination of Ara-C without compromising treatment efficacy. We conclude that the lack of cross-resistance with VAD and even HDM makes EDAP or a similar combination an attractive regiment to be formally explored in an alternating sequence with VAD in high-risk myeloma.
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PMID:Etoposide, dexamethasone, cytarabine, and cisplatin in vincristine, doxorubicin, and dexamethasone-refractory myeloma. 277 81

In this article, the clinical effects of rH-TNF on various cancer patients and the mechanism of self-induction of defense against rH-TNF cytotoxicity in tumor cells and the counter measures against this are reviewed. 1) Clinical effects of rH-TNF Intratumoral administration of rH-TNF was performed in 7 patients and clinical efficacy (PR + MR) was observed in 3/7 (42.9%). Also a reduction of leukemia cells in peripheral blood was observed in all 4 leukemia patients following intravenous (i.v.) administration of rH-TNF. Furthermore, in 2 multiple myeloma patients, the myeloma protein and plasma cells in bone marrow were reduced by i.v. administration of rH-TNF. 2) Self-induction of defense against rH-TNF cytotoxicity Investigation of the effect of TNF on RNA and protein synthesis by tumorigenic and normal cell lines showed that their synthesis in tumor cells was increased at 12 h and peaked at 24 h of incubation with TNF, while that in normal diploid fibroblast (HEL) cells was apparently unaffected by the presence of TNF. Artificial inhibition of either RNA or protein synthesis by L-M cells, upon addition of Act D or CHI increased the cytotoxic effect of TNF, thus suggesting that the elevated RNA and protein synthesis is related not to the cytotoxic reaction itself but rather to a defense mechanism. Similar incubation of HEL cells with TNF in the presence of either inhibitor resulted in the occurrence of cytotoxicity not observed with TNF alone, thus suggesting the existence of a defense mechanism in normal, TNF-resistant cells which is absent or greatly weakened in tumor cells. 3) Combination therapy of rH-TNF with various anticancer drugs. A synergistic increase in the cytotoxic effects of rH-TNF and anti-cancer drugs was demonstrated in vitro The cytotoxicity of rH-TNF against L-M cells in combination with MMC, ADM, Ara-C, ACD, DM, CDDP, VCR and 5-FU was 4 to 347 times as high as that of rH-TNF alone. These results suggest that combination therapy including rH-TNF and anti-cancer drugs may be of value in the treatment of malignancy in human patients.
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PMID:[Anti-tumor effect of human recombinant TNF]. 329 72

Tumours were raised in both congenitally athymic ('nude') Swiss mice and in neonatally thymectomized, Ara-C-protected, whole-body irradiated CBA mice by subcutaneous inoculation of cells from a variety of cultured human lines. In both types of animal, tumours tended to grow massively at the site of inoculation, with some infiltration of adjacent tissues but only rarely with evidence of metastatic spread. Tumours derived from Burkitt's lymphoma (BL) lines or from EB virus-transformed lymphoblastoid cell lines (LCL) were all classified as high grade malignant lymphomas with a limited range of appearances on conventional histological examination. In the material studied there were no consistent features distinguishing BL-derived from LCL-derived tumours. Cell lines originating from other haematopoietic malignancies tended to produce tumours interpreted as immunoblastic lymphomas though there were distinctive characteristics in some cases, such as highly convoluted or pleomorphic nuclei in the cells of some tumours derived from T-cell leukaemia lines and plasmacytoid differentiation in tumours originating from myeloma lines. Malignant cell lines of epithelial origin gave rise to tumours with the histological appearances of anaplastic carcinomas readily distinguishable from the high grade lymphomas produced by haematopoietic cells.
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PMID:The gross pathology and histological features of tumours produced by inoculation of human cell lines into immune-deprived mice. 348 63

Difficulties associated with current intensive induction regimens for multiple myeloma and uncertainty as to how to achieve optimal peripheral blood progenitor cell mobilisation (PBPC) prompted this study of an oral induction regimen, Z-Dex (oral idarubicin and dexamethasone) followed by PBPC mobilisation using four different regimens. Thirty-patients received Z-Dex (median age 56 years, range 46-66 years) including 24 patients with previously untreated disease. The overall response rate was 75% with a CR rate of 16.7% and PR rate of 75.7% in patients with previously untreated disease. We compared four mobilisation regimens: low-dose (LD) cyclophosphamide, high-dose (HD) cyclophosphamide, cis-platin/VP16 and cis-platin, Ara-C and dexamethasone (DHAP). Failure to mobilise optimal numbers of PBPCs (>1.0 x 10(6) CD34+ cells/kg and >20 x 10(4) CFU-GM/kg) was seen in two patients who received LD cyclophosphamide, in two patients who received HD cyclophosphamide and three patients who received cis-platin/VP16. No patient failed to mobilise adequate numbers of PBPCs following DHAP. In previously untreated patients, DHAP mobilised significantly more PBPC than LD cyclophosphamide (P=0.02), HD cyclophosphamide (P=0.0015) and cis-platin/VP16 (P=0.021). This study demonstrates the efficacy of Z-Dex in inducing tumour responses in patients with multiple myeloma without limiting PBPC mobilisation in subsequent dose-intensive schedules. Furthermore, we also demonstrate that DHAP is superior to cyclophosphamide (low- and high-dose) and cis-platin/VP16 in mobilising PBPCs and demonstrated a degree of tumour control.
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PMID:Peripheral blood progenitor cell mobilisation in patients with multiple myeloma following oral idarubicin and dexamethasone (Z-Dex) induction therapy. 943 37

The combination of a cyclophosphamide (CTX)-based chemotherapy regimen and interleukin-2 (IL-2) has been shown to provide synergistic effects against malignancy in animal models. We therefore conducted a phase I-II trial combining CTX-based combination chemotherapy or CTX alone with high-dose IL-2 in patients with advanced and refractory malignant disease. Fifteen patients with hemato-oncological malignancies (malignant lymphoma 8, multiple myeloma 3, solid tumor 2, leukemia 2) were enrolled in the study. Continuous high-dose IL-2 infusion was shown to be safely administered, starting as soon as recovery of white blood cell count. All patients developed rebound lymphocytosis 24-48 h after termination of IL-2 infusion. Although grade IV toxicity was observed in 5 patients (7 episodes), all side effects completely subsided. Triple chemotherapy (CTX, etoposide and Ara-C) seemed rather toxic (in this group of heavily treated patients) while CTX alone was well tolerated. Four out of 13 (31%) evaluable patients had partial response and another patient (7%) had stabilization of disease progression lasting 2-8 months. Our conclusion is that the combination of CTX and continuous infusion of IL-2 is feasible and should be investigated in patients with various malignant neoplasms.
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PMID:Continuous interleukin-2 infusion combined with cyclophosphamide- based combination chemotherapy in the treatment of hemato-oncological malignancies. Results of a phase I-II study. 979 34

Between February 1993 and November 1997, 62 patients with severe aplastic anaemia (SAA), acute myeloid (AML), acute lymphoid (ALL), or chronic myeloid leukaemia (CML) as well as two patients with NHL underwent allogeneic marrow transplantation (BMT) from HLA-identical or one-antigen mismatched sibling or unrelated donors. Patients received preparative regimens according to the baseline disease. Patients with SAA were conditioned with ATG/Cy (2 cases) and TAI/Cy (3 cases), AML, ALL and NHL with TBI/Cy (21 cases including two retransplantations) and CML with Mitobronitol/Ara-C/Cy except two patients conditioned traditionally with Bu/Cy. For GVHD prevention, patients received cyclosporin-A (CsA) with short course methotheraxe according to the Seattle protocol. Significantly better overall survival rates were associated with the Mitobronitol (DBM)/Ara-C/Cy conditioning regarded the patients as a whole. Autologous stem cell transplantation (bone marrow and/or peripheral blood) were performed in ten cases including 2 AML, 4 non-Hodgkin's lymphoma (NHL), 3 Hodgkin's disease (HD) and 1 patient with multiple myeloma (MM). Patients with AML and two patients with NHL were conditioned with TBI/Cy and the others with BEAM combined chemotherapy. Eight out of ten patients are leukaemia- or lymphoma-free survivors. One patient relapsed having conventional chemotherapy and interferon maintenance therapy. One patient died in a rapid relapse five months post-BMT.
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PMID:Haemopoietic cell transplantation activity and results: a single institution experience. 991 38

We have previously shown that selection for resistance to the anthracenes, doxorubicin or mitoxantrone, results in coselection for resistance to CD95-mediated apoptosis (Landowski et al: Blood 89:1854, 1997). In the present study, we were interested in determining if the converse is also true; that is, does selection for CD95 resistance coselect for resistance to chemotherapeutic drugs. To address this question, we used two isogenic models of CD95-resistant versus CD95-sensitive cell lines: 8226/S myeloma cells selected for resistance to CD95-mediated apoptosis; and K562 cells expressing ectopic CD95. Repeated exposure of the CD95-sensitive human myeloma cell line, 8226/S, to agonistic anti-CD95 antibody resulted in a cell line devoid of CD95 receptor surface expression and completely resistant to CD95-mediated apoptosis. Multiple clonal populations derived from the CD95-resistant cell line showed no difference in sensitivity to doxorubicin, mitoxantrone, Ara-C, or etoposide, demonstrating that cross-resistance between Fas-mediated apoptosis and drug-induced apoptosis occurs only when cytotoxic drugs are used as the selecting agent. Using the inverse approach, we transfected the CD95-negative cell line, K562, with a CD95 expression vector. Clones expressing variable levels of cell-surface CD95 were isolated by limiting dilution, and analyzed for sensitivity to CD95-mediated apoptosis and response to chemotherapeutic drugs. We show that CD95 surface expression confers sensitivity to CD95-mediated apoptosis; however, it does not alter response to chemotherapeutic drugs. Similarly, doxorubicin-induced activation of caspases 3 and 8 was identical in the CD95-sensitive and CD95-resistant cell lines in both isogenic cell systems. In addition, prior treatment with the CD95 receptor-blocking antibody, ZB4, inhibited CD95-activated apoptosis in 8226/S cells, but had no effect on doxorubicin cytotoxicity. These results show that CD95 and chemotherapeutic drugs use common apoptotic effectors, but the point of convergence in these two pathways is downstream of CD95 receptor/ligand interaction.
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PMID:Myeloma cells selected for resistance to CD95-mediated apoptosis are not cross-resistant to cytotoxic drugs: evidence for independent mechanisms of caspase activation. 1038 22

A 67-year-old man was admitted because of thrombocytopenia in May 1998. His white blood cell count was 4,900/microliter with 3.5% blasts. Laboratory findings were as follows: hemoglobin level, 10.1 g/dl; platelet count, 1.8 x 10(4)/microliter; ALT, 56 IU/l; LDH, 3,570 IU/l; IgG, 653 mg/dl; IgA, 64 mg/dl; IgM, 49 mg/dl; IgD, 674 mg/dl. Serum immunoelectrophoresis confirmed IgD lambda M-component. Bone marrow aspiration showed 79.2% myeloma cells expressing a mostly plasmablastic morphology. No mature plasma cells were found in the bone marrow. The patient received a continuous drip infusion of 20 mg/body cytarabine (Ara-C) and 50 mg/body etoposide (VP-16) for 7 days. No plasmablastic myeloma cells were detected, but 2.1% mature plasma cells were found in his bone marrow on day 20. On day 18 his platelet count exceeded 10.8 x 10(4)/microliter, and the serum IgD level fell to 210 mg/dl. Therapy consisting of melphalan, methylprednisolone and vincristine was started from day 23. No IgD lambda M-component was detectable by serum immunoelectrophoresis seven months after the diagnosis of multiple myeloma. The patient has been in complete remission as of April 2000.
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PMID:[Complete remission of plasmablastic IgD lambda multiple myeloma induced by continuous infusion of low-dose cytarabine and etoposide]. 1092 52

Gemcitabine is a cytosine arabinoside (Ara-C) analog with activity in many human tumor systems. We evaluated the drug's activity in resistant or relapsing multiple myeloma. Gemcitabine 1000 mg/m2 was administered as a 30 minute infusion on days 1, 8, and 15 of a 28-day cycle. No dose escalations were permitted and dose reductions were scheduled for hematologic toxicity. Twenty-nine eligible patients were entered into Southwest Oncology Group (SWOG)-9803. One patient received no treatment and 5 patients had inadequate response assessments. The major toxicity was hematologic with grade 3/4 neutropenia in 9 and grade 3/4 thrombocytopenia in 15 patients. No responses were seen. Stable disease was confirmed in sixteen patients (57%). Median survival was eight months. Gemcitabine as utilized in this trial has shown little activity and is not to be strongly considered for future multiple myeloma trials.
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PMID:The evaluation of gemcitabine in resistant or relapsing multiple myeloma, phase II: a Southwest Oncology Group study. 1200 87

Various chemotherapy regimens, combined with recombinant human granulocyte colony-stimulating factor(rhG-CSF) or recombinant granulocyte-macrophage CSF (rhGM-CSF) are used in cancer patients to mobilize and collect peripheral blood stem cells (PBSC). In this retrospective study, we evaluated and compared the efficacy of such regimens in 262 patients with different types of malignant diseases. The following chemotherapy regimens were applied: ifosfamide-etoposide-cisplatin or bleomycin (n = 96; mainly patients with testicular cancer); ifosfamide-etoposide plus or minus cytosine arabinoside (Ara-C) or vincristine (VCR)(n = 52; mainly patients with lymphoma); cyclophosphamide-anthracycline (n = 53; mainly patients with breast cancer); intermediate to high dose (ID-HD) cyclophosphamide (n = 37; mainly patients with breast or ovarian cancer. or multiple myeloma; and others (n = 24). rhG-CSF or rhGM-CSF, each at an average daily dose of 5 microg/kg body weight, were used in 166 and 96 patients, respectively. The study evaluated and compared the efficacy of these two cytokines. In patients receiving rhG-CSF, CD34+ cells could be collected earlier (median: day 14 versus day 16) and there was a significantly higher white blood cell count (WBC)(median 11,350 versus 5550/microl) and CD34+ cell count (median 88 versus 43/microl) at the start of apheresis, and a significantly higher CD34+ cell yield (median 7.4 x 10(6) versus 4.6 x 10(6)/kg) than in patients who receivedrhGM-CSF. Among the various chemotherapeutic regimens used, each combined with rhG-CSF, ifosfamide-etoposide plus or minus Ara-C or VCR mobilized a significantly higher number of CD34+ cells (median 119/microl) and produced a significantly higher harvest of these cells (median 13 x 10(6)/kg) than cyclophosphamide-anthracycline (median 87/microl and 7 x 10(6)/kg, respectively) or ID-HD cyclophosphamide (median 59/microl and 5 x I 0(6)/kg, respectively). Ifosfamide-etoposide plus or minus Ara-C or VCR was also superior to ifosfamide-etoposide-cisplatin or bleomycin (median 78/microl and 9 x 10(6)/kg, respectively), but at borderline significance. The outcome of PBSC mobilization and collection appeared to be negatively influenced by the number of relapses before the current salvage treatment. These data indicate that mobilization and collection of PBSCstrongly depend on the type of hematopoietic growth factor and chemotherapeutic regimen used. The data further show rhG-CSF is a more effective growth factor than rhGM-CSF and ifosfamide-etoposide-based regimens, particularly ifosfamide-etoposide plus or minus Ara-C or VCR, are highly effective regimens in mobilizing and collecting CD34+ cells.
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PMID:Impact of chemotherapy regimen and hematopoietic growth factor on mobilization and collection of peripheral blood stem cells in cancer patients. 1273 28


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