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

Administration of rHuIFN-alpha A/D and rMuIFN-gamma as single agents to tumor-bearing mice resulted in a dose-related antitumor effect in each of the six models studied. When the IFNs were given in combination, the effects varied between the tumor systems. No increase in efficacy was seen in mice bearing B16-F10 melanoma or M5076 reticulum cell sarcoma while additive antitumor activity was shown in the KA31 fibrosarcoma and P388 leukemia systems. Mice inoculated with L1210 lymphoma or colon 38 carcinoma, however, revealed enhanced efficacy which was greater than additive. The data also reveal that combination of IFNs alpha and gamma administered to normal and tumor-bearing mice resulted in toxicity which was not predicted by the appropriate doses of the single agents. These studies suggest that combination of IFNs alpha and gamma may provide greater therapeutic utility than the single agents and underscore the need for additional, carefully designed preclinical and clinical efforts.
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PMID:Efficacy and toxicity elicited by recombinant interferons alpha and gamma when administered in combination to tumor-bearing mice. 256 40

Treatment of BALB/c, C57Bl/6 or C3H/HeJ mice with non-toxic concentrations of indomethacin (75-100 micrograms/day) led to a depression of plasma neutral proteinase activity as determined with an (125I)-caseinolytic assay. Lower concentrations of indomethacin (50 micrograms/day), aspirin (1 mg/day), LiCl (3 meq/kg/day), Sulindac (100 micrograms/day), indomethacin analogs (MK-410, MK-555) or lipopolysaccharide (100 micrograms) did not induce depression in proteinase activity. Indomethacin did not directly inhibit the proteinase activity of normal plasma in vitro. The in vivo effects of indomethacin were reversible and plasma proteinase activity returned to normal values within 8 days of cessation of treatment. These results indicate that indomethacin can uniquely alter plasma proteinase homeostasis in normal mice. While effective in depressing the plasma proteinase activity of normal mice, treatment of mice bearing either the BCL1 leukemia or the B16-F10 melanoma with indomethacin did not depress the elevated plasma proteinase levels detected in tumor-bearing animals. Thus the elevation in proteinases detected in tumor-bearing animals may not be the result of increased prostaglandin synthesis and plasma proteinase activity in such disease states may be regulated differently than in normal mice. However, the ability of this potent anti-inflammatory agent to alter proteinase metabolism may contribute to its therapeutic efficacy in the management of inflammatory disease.
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PMID:Indomethacin induces the suppression of plasma neutral proteinase activity in mice: possible relationship to efficacy as an anti-inflammatory drug and induction of alterations in the immune system. 302 Feb 55

Fragile sites were analyzed in normal peripheral lymphocytes from two acute nonlymphocytic leukemia patients with t(7;11)(p15-p13;p15) leukemic cells. To induce expression of fragile sites, cultures were exposed to folate deprivation (M-F10), BrdU, distamycin A, or Hoechst 33258. Fragility at 11p15.1 was induced by distamycin A and Hoechst 33258 but was not seen in M-F10, BrdU, and control cultures. Fra(11)(p15.1) was found neither in healthy Japanese subjects (0 in 845) nor in patients with leukemia or other hematologic disorders without the t(7;11) (0 in 126). From these results, fra(11)(p15.1) can now be classified as a rare distamycin A-inducible fragile site. Furthermore, this fra(11)(p15.1) coincided with one of the breakpoints of the t(7;11)(p15-p13;p15).
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PMID:A new rare distamycin A-inducible fragile site, fra(11) (p15.1), found in two acute nonlymphocytic leukemia (ANLL) patients with t(7;11)(p15-p13;p15). 316 34

Intraperitoneal administration of Corynebacterium parvum to BALB/c, C57Bl/6 or C3H/HeJ mice lead to the induction of elevated levels of neutral proteinase activity (125I-caseinolytic activity) similar to those observed previously in animals bearing the BCL1 leukemia or the B16-F10 melanoma. Enhanced activity reached a peak at 7-14 days postinjection of the C. parvum and then gradually returned to normal levels by 20-25 days postinjection. Increased plasma proteinase activity could be induced by C. parvum whole cells or the pyridine extract residue of C. parvum but not by BCG or the pyridine extract of C. parvum. BCG did not interfere with the induction of elevated levels of activity by C. parvum. Splenectomized animals responded the same as normal mice indicating that the splenomegaly accompanying the onset of increased plasma proteinase activity was not responsible for the changes. Administration of C. parvum via a subcutaneous site rather than intraperitoneally failed to induce systemic changes in proteinase activity while still inducing splenomegaly. Treatment of animals with C. parvum before or after transplantation of the BCL1 leukemia or the B16-F10 melanoma failed to alter the course of the disease or enhance the increased proteinase activity of plasma over that observed in plasma from animals bearing tumors alone. These observations support the hypothesis that the induction of disturbances in plasma proteinase activity in tumor-bearing animals is due to alterations in host systems and that C. parvum, in contrast to BCG, contains components which can mimic the effect of some tumors on host systems.
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PMID:Corynebacterium parvum, but not BCG, induces elevations in plasma proteinase activity similar to those observed in tumor-bearing mice. 329 43

B700 is a melanoma-specific glycoprotein antigen, with a m.w. of 65,000 and an isoelectric point of 4.5; this antigen has been shown to bear significant sequence homology to a normally occurring protein, serum albumin. The production of B700 is apparently restricted to all the murine melanomas tested, since a variety of other transformed and untransformed cell lines do not contain detectable levels of this antigen. The capacity of B700 to function as a tumor-specific transplantation antigen (TSTA) is demonstrated in this study. This activity has been titrated, and it is shown that mice immunized with B700 are able to significantly inhibit the growth of B16 F10 melanomas after subcutaneous challenge; immunized mice can also inhibit the establishment and growth of experimental metastases in the lungs after i.v. challenge with B16 melanoma cells. The TSTA was found to cross-protect also against challenge with two other murine melanoma lines, JB/RH and K1735, but was specific in that the growth of two nonmelanoma lines (RBL-5 leukemia and MCA-105 sarcoma) was not affected. B700 is also shown in this study to be unrelated to other known murine tumor antigens, or to murine leukemia virus antigens. It is further shown that mice immunized with B700 produced antibodies specific to B700 that were not cross-reactive with albumins from various mammalian sources.
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PMID:Murine melanoma-specific tumor rejection activity elicited by a purified, melanoma-associated antigen. 371 69

The previous observation that the coadministration of a single dose of thymidine with the 3'-chloroethylnitrosourea analog of thymidine (3'-[3-(2-chloroethyl-3-nitrosoureido]-3'-deoxythymidine, 3'-CTNU) to mice bearing the L1210 or P388 leukemia enhanced the antitumor activity of 3'-CTNU, has led to a similar study of the potential effect on antitumor activity where thymidine, 2'-deoxyuridine, or 2'-deoxycytidine is coadministered with 1,3-bis(2-chloroethyl)-1-nitrosourea. Three levels of 1,3-bis(2-chloroethyl)-1-nitrosourea (10, 15, and 20 mg/kg) were coadministered to mice bearing the L1210 leukemia or the B16/F10 melanoma with each of the deoxyribonucleosides (2 g/kg). There was not only an increase in average days of survival of those that perished, but also a marked increase in the number of greater than 60-day survivors. The present report is a result of a determination of whether the augmented anticancer activity produced by a single injection of thymidine with 3'-CTNU was restricted to nitrosourea analogs of thymidine. The present study reveals not only that the phenomena of enhanced anticancer activity by the coadministration of thymidine can be extended to non-thymidine-containing nitrosoureas, but also that the coadministration of thymidine with 1,3-bis(2-chloroethyl)-1-nitrosourea produced an even more marked enhancement of antitumor activity than that previously observed when thymidine was coadministered with 3'-CTNU.
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PMID:Enhancement of the anticancer activity of bis(2-chloroethyl)nitrosourea in mice by coadministration of 2'-deoxyuridine, 2'-deoxycytidine, or thymidine. 379 Dec 29

Reactivity of B16 melanoma cell surface proteins with antisera to the major envelope glycoprotein, gp70, of murine leukemia viruses was assessed by radioimmunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Surface proteins from cultured monolayers of the B16 melanoma and variant lines B16-F1, B16-F1(1r6), B16-F10, and B16-F10(1r6), and from purified B16 melanoma tumor cells, contained three glycosylated components specifically reactive with gp70 antisera, with apparent molecular weights of 70,000, 80,000, and 85,000 (B16-gp70, B16-gp80, and B16-gp85). Antisera raised in syngeneic C57BL/6 mice by immunizing with X-irradiated B16, B16-F10, or B16-F10(1r6) cells immunoprecipitated only solubilized B16-gp70, B16-gp80, and B16-gp85. Absorption of mouse antiserum to B16-gp70/80/85 antigens with purified viruses from various sources indicated that antigens on all three molecules were related to endogenous AKR-type murine leukemia virus antigens. Mice hyperimmunized against melanoma cells were challenged subcutaneously with 4 X 10(4), 10(5), or 2.5 X 10(5) viable B16 or B16-F10 cells, inocula that were lethal and nonmetastatic in unimmunized mice. The lowest cell dose was rejected by 90% of immunized mice. Tumors grew in an average of 58% of immunized mice challenged with 10(5) cells, pulmonary metastases occurring in 61% of those mice. Inocula of 2.5 X 10(5) cells grew in all immunized mice, with a 60% incidence of metastasis. These studies indicate that host immunity to B16-gp70/80/85 antigens can either inhibit or stimulate B16 melanoma tumor progression.
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PMID:Multiple antigens related to the major envelope glycoprotein of murine leukemia virus expressed on B16 melanoma cells as targets of host immune response. 632 88

The oxidative modification of low-density lipoprotein by macrophages may be an important mechanism in the pathogenesis of atherosclerosis. The human monocytic leukaemia cell line THP-1, when stimulated with phorbol ester, shares many properties with human monocyte-derived macrophages. Oxidation of LDL by these cells was characterised by depletion of alpha-tocopherol, increases in thiobarbituric acid reactive substances and increases in electrophoretic mobility. The LDL particles were also converted to a form which increased accumulation of cholesteryl esters within macrophages. The oxidative mechanism appeared to be dependent upon the presence of thiols in the cellular medium. Oxidation of LDL by THP-1 macrophages, and production of thiols by these cells, were dependent upon the presence of L-cystine in the medium. Furthermore, cellular oxidation of LDL could be partially mimicked by the addition of cysteine to Hams F10 medium. Macrophage-independent oxidation of LDL, mediated by the addition of copper ions, was inhibited by cystine and cysteine in phosphate buffered saline, but not in Hams F10 medium. The glutathione content of THP-1 macrophages was also dependent upon the presence of cysteine or cystine in the medium, but inhibition of glutathione synthesis by buthionine sulfoximine did not prevent the production of thiols or the oxidation of LDL by THP-1 macrophages.
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PMID:Human (THP-1) macrophages oxidize LDL by a thiol-dependent mechanism. 888 36

Selective inbreeding of C.B17-scid/scid mouse pairs showing undetectable IgG and IgM has been carried out in order to reduce the mortality of mice by early occurrence of thymic lymphocytic leukemia and abnormal lymphocyte clones producing immunoglobulins, both of which inhibit the successful heterotransplantation of normal and neoplastic human tissues. Although the majority of C.B17-scid/scid mice showed undetectable (< 1 microgram/ml) or low level (< or = 25 micrograms/ml) of serum IgG and IgM, some produced abnormally high concentrations of IgG and IgM (> 25 micrograms/ml). The incidence of such mice showing higher levels of IgG was very high at F1 and F2 generation (10/55, 18.2%), but significantly low after the F3 generation (18/446, 4.0%, p << 0.001). Although leukemia incidence was very high at F4 to F5 generations (8/40, 20.0%), death from leukemia was not observed early in life (4-6 months after birth) at F7 to F10 generations (0/36, 0%, p < 0.01) and was very low during the age of 6-10 months after the F8 generation (11/66, 16.7% at F4 and F5 vs 4/93, 4.3% at F8-10), p < 0.01). Scid mice improved by the selective inbreeding will provide an invaluable experimental system for the heterotransplantation of normal and neoplastic human tissues.
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PMID:Reduction of leaky lymphocyte clones producing immunoglobulins and thymic lymphocytic leukemia by selective inbreeding of SCID (severe combined immunodeficiency) mice. 844 19

The ether-lipid 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (ET-18-OCH3) has anticancer activity, but systemic toxicity has restricted its therapeutic use. In this report "free" ET-18-OCH3 and a stable, well-characterized, liposome-based formulation of ET-18-OCH3 (ELL-12) were compared for in vivo toxicity in normal mice and for therapeutic efficacy in three mouse tumor model systems. The entrapment of ET-18-OCH3 in liposomes decreased the acute toxicity of ET-18-OCH3 after i.v. administration. The maximum tolerated dose for a single i.v. dose of free ET-18-OCH3 was found to be approximately 25 mg/kg, whereas the maximum tolerated dose for ELL-12 was approximately 200 mg/kg. ELL-12 was much less hemolytic in vivo than ET-18-OCH3. The therapeutic efficacy of free ET-18-OCH3 and ELL-12 was investigated against i.p. P388 leukemia, Lewis lung cancer lung metastases, and B16/F10 melanoma (lung tumor nodules) in mice. Although ET-18-OCH3 had some anticancer activity, it was found that ELL-12 was more effective than ET-18-OCH3 in all three tumor models at lower and nontoxic dose schedules. These results suggest that association of ET-18-OCH3 in stable, well-characterized liposomes transforms it into an effective antitumor agent.
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PMID:Enhanced therapeutic effects of liposome-associated 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine. 915 85


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