Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

7-Aminocephalosporin doxorubicin (AC-Dox) was condensed with monomethoxypoly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (5 kDa) or with a branched form of poly(ethylene glycol)-propionic acid N-hydroxysuccinimide ester (10 kDa), forming M-PEG-AC-Dox and B-PEG-AC-Dox, respectively. These polymer drug derivatives were designed such that doxorubicin would be released upon Enterobacter cloacae beta-lactamase (bL)-catalyzed hydrolysis. Both M-PEG-AC-Dox (IC50 = 80 microM) and B-PEG-AC-Dox (IC50 = 8 microM) were less toxic to H2981 human lung adenocarcinoma cells than doxorubicin (IC50 = 0.1-0.2 microM) and could be activated in an immunologically specific manner by L6-bL, a monoclonal antibody-bL conjugate that bound to H2981 cell surface antigens. In addition, the polymers were relatively stable in mouse plasma (< 26% hydrolysis after 24 h at 37 degrees C) and were less toxic to mice (maximum tolerated dose > 52 mumol/kg) than doxorubicin (maximum tolerated dose = 13.8 mumol/kg). Pharmacokientic studies were performed in mice bearing subcutaneous 3677 melanoma tumors. B-PEG-AC-Dox cleared from the blood more slowly than M-PEG-AC-Dox and was retained to a 2.1-fold greater extent in human 3677 melanoma tumor xenografts over a 4 h period. The intratumoral concentrations of both polymers far exceeded that of doxorubicin. Thus, the PEG-AC-Dox polymers offer the possibility of generating large intratumoral doxorubicin concentrations owing to their reduced toxicities, the amounts that accumulate in tumors, and the fact that doxorubicin is released upon beta-lactam ring hydrolysis.
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PMID:Poly(ethylene glycol)-doxorubicin conjugates containing beta-lactamase-sensitive linkers. 757 58

The development of long-circulating formulations of liposomes (S-liposomes), sterically stabilized with lipid derivatives of poly(ethylene glycol) (PEG), has increased the likelihood that these liposomes, coupled to targeting ligands such as antibodies, could be used as drug carriers to deliver therapeutic drugs to specific target cell populations in vivo. We have developed a new methodology for attaching monoclonal antibodies to the terminus of PEG on S-liposomes. A new end-group functionalized PEG-lipid derivative pyridylthiopropionoylamino-PEG- distearoylphosphatidylethanolamine (PDP-PEG-DSPE) was synthesized for this purpose. Incorporation of PDP-PEG-DSPE into S-liposomes followed by mild thiolysis of the PDP groups resulted in formation of reactive thiol groups at the periphery of the lipid vesicles. Efficient attachment of maleimide-derivatized antibodies took place under mild conditions even when the content of the functionalized PEG-lipid in S-liposomes was below 1% of total lipid. The resulting S-immunoliposomes showed efficient drug remote loading, slow drug release rates and increased survival times in circulation compared to liposomes lacking PEG. When antibodies recognizing several different tumor-associated antigens were coupled to the PEG terminus of S-liposomes a significant increase in the in vitro binding of liposomes to the target cells was observed. The binding of S-immunoliposomes containing entrapped doxorubicin to their target cell population resulted in increased cytotoxicity compared to liposomes lacking the targeting antibody.
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PMID:A new strategy for attachment of antibodies to sterically stabilized liposomes resulting in efficient targeting to cancer cells. 763 14

Antisense oligodeoxyribonucleotides targeted to the epidermal growth factor (EGF) receptor were encapsulated into liposomes linked to folate via a polyethylene glycol spacer (folate-PEG-liposomes) and efficiently delivered into cultured KB cells via folate receptor-mediated endocytosis. The oligonucleotides were a phosphodiester 15-mer antisense to the EGF receptor (EGFR) gene stop codon (AEGFR2), the same sequence with three phosphorothioate linkages at each terminus (AEGFR2S), a randomized 15-mer control of similar base composition to AEGFR2 (RC15), a 14-mer control derived from a symmetrized Escherichia coli lac operator (LACM), and the 5'-fluorescein-labeled homologs of several of the above. Cellular uptake of AEGFR2 encapsulated in folate-PEG-liposomes was nine times higher than AEGFR2 encapsulated in nontargeted liposomes and 16 times higher than unencapsulated AEGFR2. Treatment of KB cells with AEGFR2 in folate-PEG-liposomes resulted in growth inhibition and significant morphological changes. Curiously, AEGFR2 and AEGFR2S encapsulated in folate-PEG-liposomes exhibited virtually identical growth inhibitory effects, reducing KB cell proliferation by > 90% 48 hr after the cells were treated for 4 hr with 3 microM oligonucleotide. Free AEGFR2 caused almost no growth inhibition, whereas free AEGFR2S was only one-fifth as potent as the folate-PEG-liposome-encapsulated oligonucleotide. Growth inhibition of the oligonucleotide-treated cells was probably due to reduced EGFR expression because indirect immunofluorescence staining of the cells with a monoclonal antibody against the EGFR showed an almost quantitative reduction of the EGFR in cells treated with folate-PEG-liposome-entrapped AEGFR2. These results suggest that antisense oligonucleotide encapsulation in folate-PEG-liposomes promise efficient and tumor-specific delivery and that phosphorothioate oligonucleotides appear to offer no major advantage over native phosphodiester DNA when delivered by this route.
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PMID:Delivery of antisense oligodeoxyribonucleotides against the human epidermal growth factor receptor into cultured KB cells with liposomes conjugated to folate via polyethylene glycol. 772 60

We have recently demonstrated that recombinant human interleukin-2 (IL-2) can be successfully encapsulated in small (mean size, 65 nm), unilamellar, long-circulating, sterically stabilized liposomes (SSL, also known as Stealth liposomes). The present study was undertaken to assess in mice the immunomodulatory and anti-tumor effects of SSL-IL-2 in comparison with soluble, unmodified IL-2 and pegilated IL-2 (PEG-IL-2). The main findings were as follows: (a) SSL-IL-2 was significantly more effective than IL-2 in increasing leukocyte number in the blood and spleen (p < 0.05) and triggering spleen lymphokine-activated killer cell activity (p < 0.01; t test). (b) In mice with advanced metastatic carcinoma previously treated with chemotherapy (cyclophosphamide), the survival was two to six times greater following administration of SSL-IL-2 as compared with IL-2 (p < 0.05; log-rank test). Moreover, successful treatment with SSL-IL-2 required lower cumulative doses (1.25 x 10(5) vs. 2.5 x 10(5) CU) and fewer (two versus five) administrations. (c) PEG-IL-2 was a more potent immunostimulator than SSL-IL-2 in normal mice and as effective therapeutically as SSL-IL-2 in tumor-bearing mice. The former agent, however, often caused marked toxicity (up to 40% mortality in some experiments), including severe thrombocytopenia. These findings suggest that SSL-IL-2 is an immunopotentiating agent superior to IL-2 in both normal mice and in tumor-bearing mice pretreated with chemotherapy.
J Immunother Emphasis Tumor Immunol 1994 Aug
PMID:Delivery of cytokines by liposomes. II. Interleukin-2 encapsulated in long-circulating sterically stabilized liposomes: immunomodulatory and anti-tumor activity in mice. 780 26

Interleukin-12 (IL-12) is a cytokine with a wide variety of immunoregulatory activities. These include stimulation of interferon-gamma production, cytolytic activity of natural killer (NK) cells and T-cell subsets, the development of cellular immunity, and induction of maturation of Th1 cells. IL-12 also has potent anti-tumor activity in vivo. In the present study the possibility of enhanced anti-tumor activity was examined using a combination of local IL-12 by cytokine gene therapy at the tumor site, combined with systemic or local IL-2 delivery. NIH 3T3 fibroblasts transfected with the genes for both subunits of IL-12, p35 and p40, were used as the source of IL-12 therapy producing 240 HLRU/10(6) cells/48 hr. In the first part of the study the effect of different regimens of systemic IL-2 delivery with local IL-12 administration on the size and growth rate of subcutaneous MCA-105 murine sarcoma was examined. Local IL-12 alone reduced the sizes of tumors after 32 days from 163 to 26.8 mm2 (P < 0.002). Adding the longer-acting polyethylene-glycol-modified IL-2 (PEG IL-2; 30,000 IU) for 5 days prevented the development of tumors in all treated mice compared to 1/3 mice treated with PEG IL-2 alone and 3/6 mice with IL-12, but this was a highly toxic therapy and most of the animals died. Administration of 60,000 IU of IL-2 on Days 1-5 postinoculation of tumor, delivered with IL-12 gene therapy, reduced the tumor growth rate compared to animals treated with IL-2 alone (P < 0.02) or IL-12 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Administration of systemic or local interleukin-2 enhances the anti-tumor effects of interleukin-12 gene therapy. 786 76

The efficacy of tumor therapy using polyethylene-glycol-modified interleukin-2 (PEG-IL-2), alone or in combination with cyclophosphamide, was studied in advanced metastatic disease in the guinea pig. Line 10 (L10) tumor cells appeared in the axillary lymph node only 7 days after intradermal tumor-cell inoculation, and lymph-node leukocytes were almost completely replaced by tumor cells on day 28. Local treatment of the intradermally growing L10 hepatocarcinoma in the guinea pig with a relatively low dose of PEG-IL-2 resulted in regression of the primary tumor and prevention of lymph-node metastases. Therapy was completely curative (4 out of 5 animals) when started on day 7 or 14 after tumor-cell inoculation. When started on day 21, therapy was effective in only some (2 out of 5 cured) of the treated animals. Anti-tumor effects against the primary tumor and against lymph-node metastases were observed only after intratumoral (i.t.) administration of PEG-IL-2. Injection of the agent into or near lymph-node metastases in the absence of the primary tumor had no curative effect. In PBS/BSA-treated control animals the primary tumor and metastases grew progressively. In the treatment of far advanced metastatic disease, the combination of i.t. administration of PEG-IL-2 and i.p. injection of cyclophosphamide (Cy) resulted in improved anti-tumoral effects (5/5 guinea pigs were cured) when compared with monotherapy using either agent (one and none out of 5 animals cured, respectively). PBS/BSA heated controls showed progressive tumor-growth. We conclude that large primary tumors and lymph-node metastases can be treated effectively with PEG-IL-2. The i.t. route of administration is of major importance in the treatment of metastases, since administration of PEG-IL-2 near or into the lymph node had no therapeutic effect. Combination of PEG-IL-2 therapy with systemic injections of Cy significantly improved the curative effects of the treatment of advanced metastatic cancer.
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PMID:PEG-IL-2 therapy of advanced cancer in the guinea pig. Impact of the primary tumor and beneficial effect of cyclophosphamide. 792 81

The antimetastatic activities of synthetic peptides corresponding to fragments of the adhesion-related molecules, such as fibronectin and laminin, were examined. We prepared three peptides derived from the type III connecting segment domain (IIICS) of fibronectin: Glu-Ile-Leu-Asp-Val (EILDV), Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr (EILDVPST), Arg-Glu-Asp-Val (REDV), and a laminin-related peptide, Tyr-Ile-Gly-Ser-Arg (YIGSR). Each peptide inhibited the experimental tumor metastasis of B16-BL6 melanoma, while EILDV had the strongest effect. The peptides conjugated with poly(ethylene glycol) (PEG) were more effective than the unmodified peptides in molar ratio terms. A mixture composed of PEG hybrids with EILDV, REDV and YIGSR significantly inhibited tumor metastasis.
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PMID:Antimetastatic effects of synthetic peptides containing the core sequence of the type III connecting segment domain (IIICS) of fibronectin. 794 46

O6-Benzylguanine effectively inactivates the DNA-repair protein O6-alkylguanine-DNA alkyltransferase in tumor cells and has been shown to increase the cytotoxicity of chloroethylnitrosoureas. This study was undertaken to ascertain the optimal vehicle for further toxicological evaluation and eventual clinical trials of O6-benzylguanine. The solubility, metabolism, bioavailability and effectiveness of O6-benzylguanine as an adjuvant therapy with BCNU were compared using two vehicles, cremophor-EL and PEG 400. Nude mice bearing s.c. D456 MG glioblastoma xenografts were injected i.p. with 10-30 mg/kg O6-benzylguanine dissolved in either 40% PEG 400/saline or 10% cremophor-EL/saline. The number of tumor regressions noted after treatment with 10 mg/kg O6-benzylguanine followed by 12.7 mg/kg BCNU were 8/9 for the drug dissolved in PEG and 1/10 for the drug given in cremophor-EL. Using the same treatment regimen but increasing the dose of O6-benzylguanine to 30 mg/kg led to a growth delay of 45.2 and 11.5 days for the drug dissolved in PEG 400 and cremophor-EL, respectively, although the number of regressions observed were the same for both treatments. 8-[3H]-O6-Benzylguanine was more rapidly distributed to the tumor when it was delivered in PEG vehicle than when it was given in cremophor-EL. In contrast, there was a 3-fold greater amount of O6-benzylguanine in the small intestine of mice at 1 h after i.p. injection of the drug in cremophor-EL as compared with PEG 400. The rate and extent of metabolism in the liver was the same, whether the parent drug was given in PEG 400 or in cremophor-EL. These studies demonstrate that O6-benzylguanine is a more effective enhancer of the antitumor activity of BCNU when it is given in PEG 400 than when it is delivered in cremophor-EL, which may be due to a more rapid distribution of the drug to the tumor.
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PMID:Biodistribution of O6-benzylguanine and its effectiveness against human brain tumor xenografts when given in polyethylene glycol or cremophor-EL. 798 87

Macromolecular contrast media offer potential advantages over freely diffusible agents in magnetic resonance (MR) imaging outside the central nervous system. To identify an optimum molecular weight for macromolecular contrast media, the authors studied a novel macromolecular contrast agent, gadolinium diethylenetriaminepentaacetic acid polyethylene glycol (DTPA-PEG), synthesized in seven polymer (average) molecular weights ranging from 10 to 83 kd. Twenty-eight rabbits bearing V2 carcinoma in thighs underwent T1-weighted spin-echo imaging before injection and 5-60 minutes and 24 hours after injection of the Gd-DTPA-PEG polymers or Gd-DTPA at a gadolinium dose of 0.1 mmol/kg. Tumor region-of-interest measurements were obtained at each time point to determine contrast enhancement dynamics. Blood-pool enhancement dynamics were observed for the Gd-DTPA-PEG polymers larger than 20 kd. Polymers smaller than 20 kd displayed dynamics similar to those of the freely diffusible agent Gd-DTPA. Above the 20 kd threshold, tumor enhancement was more rapid for smaller polymers. The authors conclude that the 21.9-kd Gd-DTPA-PEG polymer is best suited for clinical MR imaging.
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PMID:Dynamics of tumor imaging with Gd-DTPA-polyethylene glycol polymers: dependence on molecular weight. 806 49

In an attempt to enhance the therapeutic efficacy of interleukin-2 (IL-2), recombinant human IL-2 was encapsulated either in large conventional liposomes or in small (mean diameter 65 nm), unilamellar, long-circulating, extravasating liposomes [referred to as sterically stabilized liposomes (SSLs)]. The SSL-IL-2 activity was assessed in vitro and in mice in comparison with soluble IL-2, IL-2 in conventional liposomes (non-SSL-IL-2), and pegilated IL-2 (PEG-IL-2). The main observations were as follows: (a) SSLs were far better carriers than conventional liposomes with regard to encapsulation efficiency and pharmacokinetics; (b) > 85% of IL-2 biological activity was consistently encapsulated in SSLs; (c) SSL-IL-2 was much more stable than soluble IL-2 at 4 and 37 degrees C; (d) SSL-IL-2, but not "empty" liposomes, bound in vitro to IL-2 receptor-bearing T-cells, indicating that the domain of the cytokine molecule involved in binding to the receptor is exposed on the outer liposome membrane; (e) release of IL-2 from the liposomes was not required for its in vitro biological activity; (f) plasma half-lives (t1/2 alpha, t1/2 beta) and area under the curve (AUC) of SSL-IL-2 were 10-30 times greater than those of soluble IL-2 and similar to those of PEG-IL-2; and (g) IL-2 is released from the SSLs in vivo with a t1/2 of approximately 40 min, although the SSL-IL-2s retained their steric stabilization in the plasma for > 4 h, with little liposome accumulation in the reticuloendothelial system. These data, together with the improved immunomodulatory and antitumor activity of SSL-IL-2 in mice, suggest that SSL-IL-2 might be a therapeutic agent superior to soluble IL-2.
J Immunother Emphasis Tumor Immunol 1994 Jul
PMID:Delivery of cytokines by liposomes. I. Preparation and characterization of interleukin-2 encapsulated in long-circulating sterically stabilized liposomes. 808 59


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