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Biomedical subjects

E Mayhew

Publications and source records attributed to E Mayhew.

At least 19 recordsLinked to original sources
PubMed1992

Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma.

Three different liposome types were compared for blood clearance and tissue uptake in mice bearing C-26 colon carcinoma growing either s.c. or in liver. Therapeutic experiments were performed with the liposome preparation showing the highest tumor uptake. Liposomes were composed of solid-phase phosphatidylcholine, either distearoyl phosphatidylcholine or hydrogenated soy phosphatidylcholine, and cholesterol at a 2:1 molar ratio. These liposomes were compared with similar but sterically stabilized liposomes (SL) which, in addition, contained either GM1 ganglioside or phosphatidylethanolamine derivatized with poly(ethylene glycol). Pharmacokinetic analysis of drug disposition was based on the areas under the curve for liposome-entrapped 67Ga uptake per gram of tissue up to 96 h following i.v. injection. The highest tissue area under the curve values with both liposome types were obtained in spleen, liver, and tumor. However, the sterically stabilized liposomes gave an area under the curve value 2-3-fold higher in the s.c. tumor and about 2-fold lower in liver and spleen. The therapeutic efficacy of doxorubicin (DOX) and epirubicin (EPI) encapsulated in poly(ethylene glycol)-derivatized phosphatidylethanolamine-containing liposomes was compared with that of free drug at two doses, 6 and 9 (or 10) mg/kg animal weight. Liposomes containing drug were injected either as a single dose, at different times following tumor implantation, or as three weekly doses starting 10 days after implantation. When injected as a single dose, liposome-encapsulated DOX had the maximal effect on tumor growth when injected 6 to 9 days after tumor implantation. When injected as three weekly doses, with treatment starting with a delay of 10 days, tumors which had grown to a size of approximately 0.05-0.1 cm3 regressed in groups of animals treated with either liposome-encapsulated drug (SL-DOX or SL-EPI) but continued to grow unabated in untreated mice and in mice receiving either of the free drugs. Survival of tumor-bearing animals treated with either SL-EPI or SL-DOX was significantly prolonged. Animals receiving saline, EPI, or DOX survived a mean of 50, 62, and 49 days, respectively, following tumor implantation. Eight of nine and nine of 10 animals receiving 6 and 9 mg/kg SL-EPI, respectively, survived to 120 days. Ten of 10 animals in both groups receiving 6 and 9 mg/kg SL-DOX survived to 120 days. None of the surviving animals in the SL-EPI and SL-DOX group showed any histological evidence of tumor at the conclusion of the experiment (120 days).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes.

The purpose of our study was to compare the therapeutic effects of doxorubicin in 3 different formulations: (1) in PBS, (2) in conventional liposomes composed of egg phosphatidylglycerol/egg phosphatidylcholine/cholesterol/dl-alpha tocopherol, and (3) in sterically stabilized, long-circulating "Stealth" liposomes composed of hydrogenated soy phosphatidylcholine/cholesterol/polyethylene glycol-distearoylphosphatidylethanolamine. The doxorubicin formulations were used to treat recently implanted and well-established, growing primary mouse mammary carcinomas, and to inhibit the development of spontaneous metastases from intra-mammary tumor implants. In the treatment of recently implanted primary tumors, the formulations were given in 3 i.v. injections over 15 days, starting 3 or 10 days after tumor implantation. In the treatment of well-established primary tumors, the mice received 4 i.v. injections over 22 days, starting an average 38 days after tumor implantation. In the preventive treatment against metastases, the formulations were given in 4 i.v. injections over 22 days, starting 22 days or 58 days after primary tumor implantation. The Stealth liposome formulation was significantly more effective than the conventional liposome formulation or the free drug in reducing the incidence of metastases from intra-mammary implants of tumor MC19 and tumor MC65, in curing mice with recent implants of tumor MC2A, tumor MC2B, and tumor MC65, and in increasing the 8-week survival of mice with well-established implants of tumor MC2B. It is concluded that the long circulation time of the Stealth liposome doxorubicin formulation accounts for its superior therapeutic effectiveness.

Animals↗
PubMed1992

Covalent binding of lipids to cytoskeletal proteins of mouse mammary epithelial cells.

Cytoskeletal proteins obtained from mouse mammary epithelial cells (MMEC) were found to be modified by covalent attachment of lipids. Primary cultures of MMEC were incubated in the presence of 3H-palmitate for 4 h. A cytoskeletal (CS) fraction was prepared by treatment of the cells with 1.5M KCl and 1% Triton X-100. The residual material, consisting primarily of keratin and actin filaments was exhaustively (10-20 rounds, including sonications) extracted with chloroform/methanol to remove non-covalently bound labeled lipids. The CS protein was then acid-hydrolyzed and the chloroform-soluble products subjected to thin layer chromatography (TLC). Two-thirds of the covalently bound radiolabel appeared as a very hydrophobic peak on a TLC system optimized for separation of neutral lipids. Ten percent separated into 4-5 peaks on a polar lipid TLC system. A small amount of label was traced to fatty acid-like components. Autoradiography of two-dimensional gels indicated that all the CS proteins resolvable by Coomassie blue staining were also radiolabeled. The results are discussed in terms of CS-lipid-membrane interactions.

Animals↗
PubMed1991

Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy.

The results obtained in this study establish that liposome formulations incorporating a synthetic polyethylene glycol-derivatized phospholipid have a pronounced effect on liposome tissue distribution and can produce a large increase in the pharmacological efficacy of encapsulated antitumor drugs. This effect is substantially greater than that observed previously with conventional liposomes and is associated with a more than 5-fold prolongation of liposome circulation time in blood, a marked decrease in uptake by tissues such as liver and spleen, and a corresponding increased accumulation in implanted tumors. These and other properties described here have expanded considerably the prospects of liposomes as an effective carrier system for a variety of pharmacologically active macromolecules.

Animals↗
PubMed1991

Immunotherapy of a mouse mammary carcinoma by sustained peritumor release of IL-2.

The purpose of this study was to compare the local and systemic therapeutic effects of Interleukin-2 (IL-2) used in 3 different preparations: suspended in PBS, suspended in 2% agar, and entrapped in multi-lamellar liposomes suspended in 2% agar. The liposomes were composed of phosphatidylglycerol and phosphatidylcholine in a 1:4 molar ratio. The net release of IL-2 in vitro (by ELISA assay) at 37 degrees C, measured at 4 hr, 2 days, and 10 days, was 50%, 75%, and 100% from agar, and 8%, 22%, and 33% from liposomes in agar. In the therapeutic tests, the IL-2 preparations were injected close to s.c. implants of the MC2 mouse mammary carcinoma. Four injections at weekly intervals of IL-2 in agar had as much local and systemic (against uninjected contralateral tumor implants in treated mice) therapeutic effect as the same total amount of IL-2 in PBS given in 20 daily injections over 4 weeks. The IL-2 liposome-gel preparation was most effective (p less than 0.05), probably due to the more sustained release of IL-2. Three injections of this preparation gave a fixed and sustained peritumor release of IL-2 which, at sub-toxic levels, resulted in both local and systemic therapeutic effects.

Animals↗
PubMed1991

Effect of acute versus chronic Trichinella pseudospiralis infections on systemic cell-mediated immunity.

Infection of the mouse with Trichinella pseudospiralis is accompanied by pronounced suppression of host inflammatory response. This study examines the effects of infection with this parasite on several key elements in cell-mediated immunity. Early down-regulation of host granulomatous response to subcutaneously implanted cotton string and delayed-type hypersensitivity (DTH) response to trinitrochlorobenzene (TNCB) was followed later during infection by normalization of these parameters compared to that seen in uninfected mice. Cytotoxic T lymphocyte responses to tumor-specific antigens expressed on the syngeneic P91 mastocytoma were depressed early following infection with T. pseudospiralis relative to that seen in uninfected mice but were similar in these two groups during the later stages of infection. Down-regulation of the components of cell-mediated reaction examined herein accompanied the presence of migratory larvae in the host.

Acute Disease↗
PubMed1990

Lipids noncovalently associated with keratins and other cytoskeletal proteins of mouse mammary epithelial cells in primary culture.

Lipids noncovalently associated with cytoskeletal (CS) proteins of mouse mammary epithelial cells (MMEC) grown in primary culture were analyzed. A CS fraction, prepared by subjecting MMEC to 1.5 M KCl and 1% Triton X-100 in phosphate buffered saline (pH 7.4), was extracted 4-6 times with chloroform/methanol. Thin-layer chromatography (TLC) indicated that in comparison to whole cell lipid extracts, CS lipids consisted mostly of neutral lipids, especially triacylglycerols and, possibly cholesteryl esters. TLC analysis of chloroform/methanol CS extracts prepared from MMEC that had been incubated 4 h in [3H]palmitate revealed similar results, with the majority of label appearing in triacylglycerols and other neutral lipids. By autoradiography of sodium dodecyl sulfate polyacrylamide gels, all of the major CS proteins appeared labelled. The major regions of autoradiographic density of the gel were excised, the protein solubilized, and the lipids extracted and subjected to TLC. Most of the radiolabel appeared at the origin and ion front and resolved as neutral lipids. In contrast, keratins of 54-55 kDa and 46 kDa appeared to be associated noncovalently with a higher ratio of polar lipids (possibly phospholipids) to nonpolar (neutral lipids). Very little radioactivity, mostly neutral lipid, was associated with actin. A previously unidentified CS component of 30 kDa had primarily noncovalently bound neutral lipid. The results are discussed in terms of the apparent interactions of keratin filaments with the plasma membrane, nuclear envelope and cytoplasmic organelles.

Animals↗
PubMed1990

P-glycoprotein expression and modulation of cell-membrane morphology in adriamycin-resistant P388 leukemia cells.

Electron microscopy of cultured P388 leukemia cells revealed morphological differences between the Adriamycin-resistant (P388/ADR) and -sensitive (P388/0) cell lines. P388/ADR cells showed longer villus-like protrusions and large foldings of the plasma cell membrane, whereas P388/0 cells had only short membrane protrusions. Western blot analysis of cells revealed the increased expression of a glycoprotein of 170-180 kDa (P-glycoprotein) in P388/ADR cells as compared with P388/0 cells, which is consistent with the findings of other studies. A modulation of the membrane morphology of in vitro P388/ADR cells was evident from one i.p. in vivo passage for 10 days, by a reversion to the non-ruffled sensitive-cell morphology. Long-term P388/ADR culture cells showed a reduction in membrane folding with as little as a 4-h exposure to the peritoneal ascitic fluid obtained when the tumor was harvested. However, there was no alteration in the expression of P-glycoprotein or in the sensitivity to Adriamycin in either of the P388 cell lines when grown in vivo or when exposed to ascites fluid from an i.p. tumor. Thus, the modulation of membrane morphology was related to the tumor cell environment rather than the abundance of P-glycoprotein in the plasma membrane.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

Antiviral and antiproliferative properties of liposome-associated human interferon-gamma.

Recombinant human interferon-gamma (rHuIFN-gamma) was associated with liposomes in an attempt to improve its therapeutic efficiency. It was associated with liposomes composed of phosphatidylserine (PS) and phosphatidylcholine (PC) at a ratio of 3:7, and of PS:PC and cholesterol (CHOL) at a ratio of 1:4:5 with efficiencies of 13% and 21%, respectively. The lipid composition influenced the antiviral activity of the liposome-complexed IFN-gamma tested against vesicular stomatitis virus. IFN associated with PS:PC liposomes was fully bioavailable and degraded by trypsin treatment. In contrast, PS:PC:CHOL-IFN was resistant to trypsin, and appeared latent as its full biological activity was seen only after disruption of the liposomes with detergent. Four human tumor cell lines were exposed to free and liposome-associated IFN-gamma. The growth of three solid tumor lines (colon, bladder, and lung) was inhibited by similar concentrations of free IFN and PS:PC-IFN. In contrast, less PS:PC-IFN than free IFN was needed to inhibit histiocytic lymphoma cells. Higher concentrations of PS:PC:CHOL-IFN than of free IFN were needed to inhibit growth of all four cell lines. The specificity of these effects of liposome-associated IFN-gamma were shown by their partial or complete neutralization by antibody to IFN-gamma. When liposome-IFN complexes of either type were stored at 4 degrees C, 30% of the IFN activity remained after 7 days; thereafter, decay was minimal over the next 3 weeks. These data show the formation of stable HuIFN-gamma-liposomes and indicate that the lipid components of these complexes influence their antiviral and antiproliferative activity for several different cell types.

Antineoplastic Agents↗
PubMed1990

Free and liposomal doxorubicin treatment of intraperitoneal colon 26 tumor: therapeutic and pharmacologic studies.

Intraperitoneal (i.p.) chemotherapy is being investigated as an adjunct to surgery to kill residual cancer cells, inhibit cancer cell seeding, local recurrence, and metastases for ovarian, gastric, and colon cancers. In this report, the therapeutic effects of Doxorubicin (Dox) and liposome-entrapped Dox (Dox-Lip) against i.p. mouse colon 26 (C26) tumor were compared. It was found that Dox-Lip was less toxic than Dox after i.p. administration in non-tumor bearing animals. I.P. Dox and Dox-Lip significantly inhibited the growth of C26 tumor when the treatment was initiated 1 day after tumor cell inoculation, but both administration forms were ineffective against well-established (8-day) tumors. Multiple dose schedules did not improve the therapeutic response. Dox-Lip was not therapeutically superior to Dox at equal doses or at approximately equi-toxic doses. In addition, the relative retention of Dox and Dox-Lip in the peritoneal cavity and their plasma pharmacokinetics were investigated. It was found that Dox levels in the peritoneal cavity were maintained for longer periods after i.p. Dox-Lip was administered. However, the results show that maintenance of elevated drug levels in the peritoneal cavity does not necessarily lead to increased therapeutic effects.

Animals↗
PubMed1989

Therapy of central nervous system leukemia in mice by liposome-entrapped 1-beta-D-arabinofuranosylcytosine.

Studies were undertaken to determine the therapeutic effects of liposome-encapsulated 1-beta-D-arabinofuranosylcytosine (lip-ara-C) against intracranial L1210 leukemia. The effects of administration route, drug dosage, liposome type, and tumor load on therapeutic efficacy were also studied. One hundred % mice were cured after a single intracranial 40 mg/kg dose of lip-ara-C, dependent on tumor load. Intracranial lip-ara-C was more effective than i.v. lip-ara-C. A single i.v. dose of lip-ara-C was therapeutically superior to 5-day i.v. infusion of the free drug. Intracranial or i.v. lip-ara-C at therapeutic doses resulted in less systemic toxicity than i.v. infusion of free ara-C, suggesting possible use of lip-ara-C as an adjunct to treatment of central nervous system leukemia.

Animals↗
PubMed1989

Immunospecific targeting of cytosine arabinonucleoside-containing liposomes to the idiotype on the surface of a murine B-cell tumor in vitro and in vivo.

A new tumor model is described that is suitable for the evaluation of antibody-directed drug-delivery protocols and a modification in the procedure for covalently coupling antibody to the surface of drug-containing liposomes is presented. These immunospecific liposomes containing cytosine arabinonucleoside (Ara-C) have been tested in vitro and in vivo for their ability to kill a B-cell tumor. The target of the immunospecific-Ara-C liposomes is the idiotype associated with an antigen-specific immunoglobulin receptor on the cell surface of a murine B-cell hybrid (2C3). Affinity-purified antibodies specific for the idiotype were covalently coupled to modified lipid on the surface of the large unilamelar liposomes containing drug. These liposomes were shown to kill idiotype-positive 2C3 cells in vitro, but not idiotype-negative variants of this same cell line. It was also established in vitro that the drug-containing liposomes were at least 40 times more efficient than free Ara-C in the killing of the tumor cells. The 2C3 tumor was also propagated in vivo following the i.p. administration of tumor cells. The tumor grew initially as multiple foci within the peritoneum and subsequently spread to the spleen. Tumor-bearing mice were treated either with free Ara-C or with immunospecific liposomes containing Ara-C. Tumor growth in the primary tumor nodules and in the spleen was monitored by the administration of bromodeoxyuridine to the tumor-bearing animals followed by the immunofluorescent staining of cells with a monoclonal anti-bromodeoxyuridine antibody to estimate the proportion of cells in S phase. Our data from five out of seven animal experiments shows that the immunospecific-Ara-C liposomes, but not free drug, reduced tumor growth in the spleen. However, neither the liposomes containing drug nor the free drug were able to alter the growth of the primary tumor nodules growing in the peritoneal cavity. These results suggest that immunospecific-Ara-C containing liposomes may be useful in conjunction with other cytoreductive protocols in controlling tumor growth or preventing the spread of the tumor to other sites, but that immunospecific-Ara-C containing liposomes by themselves are not likely to eliminate an established tumor in vivo. We also demonstrate here that the administration of immunospecific-Ara-C containing liposomes in an animal having high levels of circulating tumor-associated antigen (i.e., IgG containing the idiotype) represents a potential clinically relevant hazard which must be considered when designing antibody-directed drug-delivery protocols.

Animals↗
PubMed1989

A mechanism for anti-asialo GM 1 antibody-induced anaphylactoid response in mice infected with Trichinella pseudospiralis.

Intravenous injection of anti-asialo GM 1 antibody into mice infected with Trichinella pseudospiralis resulted in rapid acute illness or death accompanied by a dramatic rise in hematocrit values in these animals. The described antibody-induced changes were reversible by intravenous infusion of Hanks' balanced salt solution (HBSS). These effects were not seen in uninfected mice or in Trichinella spiralis-infected mice injected with anti-asialo GM 1 antibody. Viability of T. spiralis or T. pseudospiralis infective L1 larvae, both isolated worms and those housed in muscle, was unaffected by exposure to anti-asialo GM 1 antibody and complement. Infectivity of larvae of T. pseudospiralis decreased significantly following exposure to anti-asialo GM 1 antibody. Release of protein by T. pseudospiralis infective L1 larvae during incubation in the presence of anti-asialo GM 1 antibody was significantly greater than that released by worms incubated in normal rabbit serum or HBSS. Protein released by infective L1 larvae of T. pseudospiralis was identified as Trichinella excretory/secretory antigens by immunoblot. Intravenous injection of T. pseudospiralis excretory/secretory products resulted in anaphylaxis in T. pseudospiralis-infected mice but not in uninfected or T. spiralis-infected mice. Excretory/secretory product-induced anaphylactoid response also was reversible by the intravenous injection of HBSS or by injection of an antihistamine. Significantly higher levels of total IgE were observed in sera from mice infected with T. pseudospiralis compared to uninfected or T. spiralis-infected mice. Binding of anti-asialo GM 1 antibody to the surface of T. pseudospiralis muscle larvae induced release of excretory/secretory antigen by the parasite.(ABSTRACT TRUNCATED AT 250 WORDS)

Anaphylaxis↗
PubMed1988

Alterations in murine host defense functions by adriamycin or liposome-encapsulated adriamycin.

Peritoneal exudate cells (PEC) from C57BL/6 mice were collected on different days following an i.p. injection of Adriamycin (10 mg/kg) as free drug (ADM) or encapsulated in multilamellar liposomes (ADM/Lip). Macrophages harvested from mice at various times (Days 4-14) after either drug treatment were responsive to in vitro lipopolysaccharide induction of tumoricidal activity, maximum response being seen on Day 7. In addition, 18 days after treatment, significant macrophage tumoricidal activity was observed only in the ADM/Lip-treated group. When supernatants from cultures of PEC obtained 7 days after treatment were assayed for interleukin 1 following lipopolysaccharide stimulation, activity was found with both ADM- and ADM/Lip-treated cells. Without lipopolysaccharide stimulation, only PEC from ADM-treated mice elaborated factor(s) with interleukin 1-like activity. Both ADM and ADM/Lip induced significant PEC-natural killer (PEC-NK) activity by Day 4, while the ADM/Lip treatment sustained PEC-NK activity more effectively than free drug at later time points (7 or 11 days posttreatment). Drug-induced PEC-NK activity (Day 7) was (a) ablated by treatment in vitro with anti-asialo GM1 antibody and complement, and (b) associated with a population of PEC nonadherent to plastic. A transient suppression of splenic NK activity was seen 4 days following either ADM or ADM/Lip administration with recovery to control level by Day 7. These data demonstrate that following ADM or ADM/Lip administration some of the changes necessary for macrophage tumoricidal activation must have occurred in vivo. Liposome encapsulation of ADM extended the duration of ADM-induced augmentation of certain host defenses.

Animals↗
PubMed1988

The effects of verapamil and a tiapamil analogue, DMDP, on adriamycin-induced cytotoxicity in P388 adriamycin-resistant and -sensitive leukemia in vitro and in vivo.

DMDP [N-(3,4-dimethoxyphenethyl)-N-methyl-2-(2-naphthyl-m-dithane- 2-propylamine] a recently developed calcium antagonist analogue, caused a greatly increased intracellular retention of adriamycin and concomitant enhanced cytotoxicity in adriamycin-resistant P388 leukemia cells in vitro. These effects of DMDP were greater than those of another calcium channel blocker, verapamil, and occurred at one-half the dosage levels. Only slight enhancement in adriamycin toxicity was observed for either of these agents in the adriamycin-sensitive parental cell line. However, no significant therapeutic potentiation of adriamycin activity occurred with either verapamil or DMDP treatment in vivo. In vivo maximum DMDP tumor intracellular concentrations, as analyzed by HPLC, were the same in vitro tumor cell levels required to overcome adriamycin resistance. This inability to overcome drug resistance in vivo at acceptable levels of host toxicity is not only a function of maintaining necessary calcium antagonist concentrations in resistant tumor cells.

Animals↗
PubMed1988

Trichinella pseudospiralis larvae express natural killer (NK) cell-associated asialo-GM1 antigen and stimulate pulmonary NK activity.

Natural killer (NK) cell function was evaluated in mice infected with either Trichinella pseudospiralis or T. spiralis larvae. T. pseudospiralis-infected mice consistently demonstrated augmented pulmonary NK cell-mediated clearance of YAC-1 tumor cells in vivo but failed to display enhanced splenic NK cell-mediated lysis of the same tumor cells in vitro. Attempts to alter NK cell function in vivo by the injection of anti-asialo-GM1 antibody resulted in anaphylaxis and death of the hosts infected with T. pseudospiralis but not of mice infected with T. spiralis. Immunofluorescence studies demonstrated that larvae of both species bound large quantities of anti-asialo-GM1 antibody but did not react with another NK-associated antibody, anti-NK-1.1. Even though anti-asialo-GM1 antibody reacted with larvae of both species, intravenous injection of antibody elicited anaphylaxis only in hosts that were infected with T. pseudospiralis.

Adrenal Cortex Hormones↗
PubMed1987

Toxicity of non-drug-containing liposomes for cultured human cells.

The effects of non-drug-containing liposomes of different compositions and sizes on the proliferation of nine cancer-derived and one normal cultured human cell lines were determined. Stearylamine- and cardiolipin-containing liposomes were toxic (ID50) at 200 microM liposomal lipid concentrations or less, whereas phosphatidylglycerol- and phosphatidylserine-containing liposomes were toxic in the range 130-3000 microM. Phosphatidylcholine or dipalmitoylphosphatidylcholine liposomes were not toxic at 3000-4000 microM. In general, small liposomes were more toxic than large ones. The results indicate that there are wide variations in toxicity of non-drug-containing liposomes for cultured human cells. The potential for nonspecific toxicity due to the liposomes themselves should be carefully considered if human administration of drug-containing liposomes is to be done.

1,2-Dipalmitoylphosphatidylcholine↗