Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of liposome entrapment in modulating the cytotoxicity of a lipophilic cisplatin derivative was assessed. cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum++ +(II) (NDDP) was tested in suspension (free NDDP) or entrapped in multilamellar vesicles composed of dimyristoylphosphatidyl choline and dimyristoylphosphatidyl glycerol (L-NDDP). Against LoVo colon carcinoma cells sensitive to cisplatin, L-NDDP was two times more cytotoxic in vitro than free NDDP and cisplatin (Do 7 microM for L-NDDP, 15 microM for free NDDP, and 16 microM for cisplatin). Against LoVo cells resistant to a concentration of 3 micrograms/ml of cisplatin, L-NDDP was three times more cytotoxic than free NDDP and cisplatin (Do 14 microM for L-NDDP, 45 microM for free NDDP, and 48 microM for cisplatin). In in vivo studies, free NDDP was less potent and less active than L-NDDP against i.p. L-1210 leukemia (free NDDP, optimum %T/C 148 at a dose of 75 mg/kg; L-NDDP, optimum %T/C 185 at a dose of 25 mg/kg) and i.p. L1210/PDD leukemia (free NDDP, optimum %T/C 128 at a dose of 50 mg/kg on Days 1, 5, and 9; L-NDDP, optimum %T/C 200 at a dose of 12.5 mg/kg on Days 1, 5, and 9). Free NDDP administered i.v. was inactive against liver metastases of M5076 reticulosarcoma (%T/C 102) while L-NDDP showed significant activity (%T/C 140). The single dose i.v. LD50 in mice of free NDDP and L-NDDP were similar (79.4 mg/kg for free NDDP and 64.5 mg/kg for L-NDDP). These studies show that NDDP is a liposome-dependent drug since it can only be satisfactorily formulated in the liposomal form and since the liposomal carrier plays a crucial role in determining its antitumor activity.
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PMID:Increased cytotoxicity and reversal of resistance to cis-diamminedichloro-platinum(II) with entrapment of cis-Bis-neodecanoato-trans-R,R-1,2-diaminocyclohexaneplatinum (II) in multilamellar lipid vesicles. 339 3

Tricyclic nucleoside phosphate (TCN-P) was selected for clinical trials because of its unusual chemical structure and activity against L1210 murine leukemia and MX-1 mammary xenograft. Inhibiting DNA synthesis, TCN-P was more toxic during S-phase of cell cycle. A phase I study was conducted in 24 patients with advanced solid cancers. The drug was given as a slow i.v. injection over 5 min on Days 1, 8, 15, and 22 of a 42-day cycle with a 2-week rest. Five dose levels ranging from 12 to 96 mg/m2 were studied with 3 to 12 patients treated at each level; a total of 106 doses was administered. The major hematological toxicity was thrombocytopenia, with a median nadir occurring at Day 34 of the cycle and first appearing at doses greater than 24 mg/m2. Anemia was seen at each dose level occurring between Days 8 and 34. Non-myelosuppressive toxic effects included stomatitis, anorexia, transient fever, nausea and vomiting, and dose-limiting hyperglycemia and diarrhea. The highest tolerated dose was 48 mg/m2. Plasma, pleural fluid, urine, and tissue samples were analyzed for TCN-P and tricyclic nucleoside (TCN) in selected patients by high-performance liquid chromatography. Plasma decay curves revealed extended retention of both TCN and TCN-P. Autopsy specimens obtained 61 days after therapy showed the highest residues of TCN-P in liver metastases and of TCN in gall bladder, bile, and pancreas. No drug was detected in urine samples of two patients. Prolonged retention and erratic plasma levels of the drug are probably due to extensive enterohepatic circulation, as well as repeated interconversion between TCN-P and TCN within cells. This weekly schedule produced unexpected clinical toxicity and should not be pursued.
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PMID:Phase I evaluation and clinical pharmacology of tricyclic nucleoside 5'-phosphate using a weekly intravenous regimen. 369 29

CLM developed in 60 of 526 patients (11%) with SCLC seen at the NCI between August 1969 and June 1980. Life table analysis revealed an overall 25% risk of CLM at 3 years. CLM was diagnosed during all phases of the patients' clinical course, but the majority (83%) were cases diagnosed at the time of progressive systemic disease. Univariate log rank analysis indicated that pretreatment factors associated with the development of CLM included: involvement of the brain, spinal cord, bone marrow, liver or bone; extensive disease; and male sex. Patients who did not obtain a complete response to systemic therapy were at greater risk of developing CLM than complete responders. Multivariate analysis of these factors indicated that liver metastases were most strongly associated with the time to development of CLM, followed in order of importance by bone and CNS metastases. Patients usually presented with signs and symptoms reflecting involvement of multiple areas of the neuraxis including the cerebrum, cranial nerves and spinal cord; 51 of the 60 patients had intracerebral metastases and 27 had spinal cord lesions during their clinical course. Autopsy features including focal or diffuse involvement of the leptomeninges with infiltration of the Virchow-Robin spaces were similar to meningeal lymphoma and leukemia, except that CLM was rarely the sole manifestation of CNS tumor. Median survival following the diagnosis of CLM was 7 weeks. However, most deaths were attributed to systemic disease, and treatment with intrathecal chemotherapy and irradiation often provided palliation. With the increased awareness of this complication, an antemortem diagnosis increased from 39% prior to 1977, to 88% of patients after 1977.
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PMID:Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience. 627 48

Transformation of hematopoietic cells by the p210bcr/abl tyrosine kinase appears to require the expression of a functional MYC protein, suggesting that simultaneous targeting of BCR-ABL and c-myc might be a rational strategy for attempting treatment of Phil-adelphia leukemia. To test this hypothesis, severe combined immunodeficiency mice injected with Philadelphia leukemic cells were treated systemically with equal doses of bcr-abl or c-myc antisense oligodeoxynucleotides (ODNs) or with both ODNs in combination. Compared with the mice treated with individual agents, the disease process was much slower in the group treated with both ODNs, as revealed by flow cytometry, clonogenic assay, and reverse transcriptase-polymerase chain reaction analysis to detect leukemic cells in mouse tissue cell suspensions, and by enumeration of liver metastases. The retardation of the disease process was positively correlated with a markedly increased survival of leukemic mice treated with both ODNs. These data demonstrate the therapeutic potential of targeting multiple cooperating oncogenes.
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PMID:Leukemia treatment in severe combined immunodeficiency mice by antisense oligodeoxynucleotides targeting cooperating oncogenes. 750 9

Detection of disseminated leukemia within organ is often very difficult and might lead to underestimation of the metastatic load. Therefore, we transduced the mouse ESb T lymphoma with the bacterial lacZ gene, which allowed us to follow metastasis at the single cell level. Intradermal primary tumor growth of lacZ transduced ESbL cells (L-CI.5s) comprised three phases: an initial expansion phase (day 0 to 9, increase from 0 to 8 mm, tumor diameter), a plateau phase (day 9 to 20, constant diameter of 8 mm and necrosis), and a second expansion phase (day 20 to 30, increase from 8 to 15 mm). Liver metastasis could already be detected at day 3 and maintained at that level until day 23, where exponential expansion started. A distinct mosaic-like metastasis pattern developed, with preferential localization of tumor cells to the periportal areas of the liver in immunocompetent animals. In contrast, in immunocompromised mice, primary tumor growth and metastasis were progressive and metastasis appeared as diffuse or focal/clustered. Healthy animals surviving a tumor cell inoculum of a variant cell ESbL-CI.5) with a reduced metastatic potential carried low levels of possibly dormant tumor cells in the bone marrow. Thus, this study showed that host immunocompetence determines to a large extent kinetics and load of spontaneous liver metastases and even influences the pattern and localization of disseminated lymphoma cells.
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PMID:Pattern and load of spontaneous liver metastasis dependent on host immune status studied with a lacZ transduced lymphoma. 794 89

High-molecular-mass alkaline phosphatase (H-Mr AP) was detected in sera from children with solid tumors without liver metastases. H-Mr AP activities were determined by a liquid chromatographic and an electrophoretic method. In 5 out of 10 cases with solid tumors--Ewing sarcoma (n = 2), neuroblastoma (n = 2), and rhabdoid tumor (n = 1)--H-Mr AP activities ranged from 3.1-40.4 U/L and 3.1-16% of total serum AP activity. In sera of patients with leukemia (n = 18) H-Mr AP was not detectable. After the treatment of the sera with papain and phosphatidylinositol-specific phospholipase C, which release membrane-associated AP from membrane particles, H-Mr AP was no longer detectable. These results indicate that H-Mr AP in the sera of patients with solid tumors may derive from increasing cell shedding of the tumor cells with elevated levels of membrane fragments in serum, which is a well known phenomenon in liver tumors. H-Mr AP was not more detectable in the serum after successful tumor treatment. These data suggest that H-Mr AP was produced by the tumors and that this parameter may be a serological marker for some solid tumors even in the presence of normal total AP serum activity.
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PMID:High-molecular-mass or macromolecular alkaline phosphatase in sera of children with solid tumors. 815 5

Graft-versus-leukemia (GvL) has been shown to be an important immune-mediated antitumor effect in hematologic malignancies. It is still unknown whether such an immunemediated antitumor effect has clinical implications in patients with solid tumors. A 32-year-old woman with inflammatory breast cancer received a bone marrow transplant (BMT) from her HLA-identical sibling. During graft-versus-host disease (GvHD) cytotoxic T lymphocytes were grown and tested in a chromium-release assay against B and T lymphocytes of the patient and donor and against a panel of breast cancer cell lines. Resolution of liver metastases was observed simultaneously with clinical GvHD in the first weeks after transplant. In addition, minor histocompatibility antigen (MiHA)-specific and major histocompatibility complex (MHC) class I antigen-restricted cytotoxic T lymphocytes recognizing breast carcinoma target cells were isolated from the blood of the patient. Pretreatment of such target cells with tumor necrosis factor (TNF)-alpha but not with interferon (IFN)-alpha or IFN-gamma increased susceptibility of these cells to lysis by cytotoxic T lymphocytes. Clinical course and in vitro results suggest that a graft-versus-tumor (GvT) effect might exist after allogeneic BMT for breast cancer. However, clinical experience on a larger scale would be required to determine the clinical efficacy of GvT effects in patients with solid tumors.
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PMID:Evidence for a graft-versus-tumor effect in a patient treated with marrow ablative chemotherapy and allogeneic bone marrow transplantation for breast cancer. 869 72

T-cell-mediated antitumor effects play an important role clinically in allogeneic graft-versus-leukemia (GvL) reactivity, whereas T-cell-mediated antihost effects are associated with a risk of developing graft-versus-host (GvH) disease. GvL and GvH were compared in an animal tumor model system after the systemic transfer of allogeneic antitumor immune T lymphocytes from B10.D2 [H-2d; minor lymphocyte-stimulating antigen (Mls)b] mice into ESb-MP tumor-bearing or normal DBA/2 (H-2d; Mls(a)) mice. Here we demonstrate that this T-cell-mediated therapy involves the formation of clusters of donor CD4 and CD8 T cells with host macrophages, in particular, with a subpopulation expressing the lymphocyte adhesion molecule sialoadhesin. DBA/2 mice and the derived tumor ESb-MP express viral superantigen 7 (Mls(a)), an endogenous viral superantigen that is absent from B10.D2 mice. To test the contribution of viral superantigen 7-reactive Vbeta6 donor T cells in the GvL-mediated eradication of liver metastases, we performed immunohistological and transmission electron microscopy studies. Vbeta6+ CD4 and CD8 T cells from B10.D2 donors formed tight clusters with host sialoadhesin-positive macrophages, and transmission electron microscopy pictures revealed direct membrane-membrane interactions between T cells and macrophages. Clusters were more abundant and consisted of more cells in tumor-bearing hosts (GvL model) than in non-tumor-bearing hosts (GvH model). In addition, Vbeta6 T cells within the clusters showed a strong proliferation activity, indicating stimulation. Moreover, in an in vitro tumor cytostasis assay, primed as well as nonprimed purified Vbeta6 T cells from donor mice were able to inhibit the proliferation of superantigen-expressing ESb-MP lymphoma cells. This suggests that the transferred superantigen-reactive Vbeta6 T cells contribute to the eradication of metastases. The observed cell clusters might be sites for antigen presentation and the activation of tumor-reactive T cells.
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PMID:Graft-versus-leukemia reactivity involves cluster formation between superantigen-reactive donor T lymphocytes and host macrophages. 986 26

Hepatic metastases are a major cause of morbidity and mortality for patients with colorectal cancer (CRC). The rationale for hepatic arterial chemotherapy has both an anatomical and pharmacological basis. Several randomized clinical studies of fluoropyrimidine showed higher response rates in all trials when the drug was given as an hepatic arterial infusion (HAI) versus systemic administration. However, the studies did not accurately define survival for the following reasons: (1) some allowed a crossover; (2) some were too small; and (3) some used inadequate systemic chemotherapy. Patients who have failed to respond to previous systemic chemotherapy have an approximately 50% response rate with HAI treatment. Hepatic toxicity, especially biliary sclerosis, is the dose-limiting toxicity, occurring in 6% to 25% of patients. Adding dexamethasone to HAI fluoropyrimidine decreases the hepatobiliary toxicity. The therapeutic benefit of HAI in one study was also demonstrated by an increased time with normal quality of life. To truly define the role of regional therapy in patients with CRC confined to the liver, the current Cancer and Leukemia Group B (CALGB) study is randomizing patients to HAI versus systemic therapy without a crossover to demonstrate if HAI improves survival and/or quality of life in addition to response rates.
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PMID:Hepatic arterial chemotherapy in metastatic colorectal patients. 1052

In a murine tumor model, complete tumor remission is achievable at even advanced metastasized stages by transfer of immune T cells from donor B10.D2 (H-2d, Mls(b)) into tumor-bearing DBA/2 (H-2d, Mls(a)) mice. We showed previously that this graft-versus-leukemia (GvL) effect is dependent on synergistic interactions of transferred CD4+ and CD8+ T cells with host sialoadhesin (SER)-positive macrophages. We now show that the CD40-CD40L (CD154) interaction is involved in the induction of inducible nitric oxide synthase (iNOS) expression during adoptive immunotherapy (ADI). We demonstrate that during ADI, the level of CD40 expression in the liver becomes significantly augmented in comparison to livers of tumor-bearing, untreated animals. CD40 expression is found mostly on SER+ macrophages and to a lesser extent on dendritic cells (DCs). In GvL animals, more SER+ macrophages express iNOS than untreated animals. iNOS expressing cells are found in close proximity to apoptotic cells, at early time points of the therapy in areas of metastasis, and at late stages around portal veins, where CD4+ and CD8+ T lymphocytes form clusters with SER+ macrophages. Blocking of CD40L in vivo at days 5 and 20, when all iNOS+ cells express CD40, leads to significantly reduced CD40 and iNOS expression as well as to a marked inhibition of the therapeutic effect. These data provide functional and in situ evidence that the increased CD40 and iNOS expression observed during ADI contribute to the eradication of liver metastases and to the clearance of donor lymphocytes from the liver.
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PMID:Functional and in situ evidence for nitric oxide production driven by CD40-CD40L interactions in graft-versus-leukemia reactivity. 1081 24


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