Biomedical subjects

E Mayhew

Publications and source records attributed to E Mayhew.

At least 37 records · Page 2Linked to original sources

PubMed1997

Local inhibition of natural killer cell activity promotes the progressive growth of intraocular tumors.

PURPOSE: To study the effect of aqueous humor (AH)-mediated inhibition of natural killer (NK) cell activity on intraocular tumor progression. METHODS: Two NK-sensitive tumors, RMA-S lymphoma and OCM-3 uveal melanoma, were tested in vitro for susceptibility to NK cell-mediated lysis in the presence or absence of AH in conventional cytotoxicity assays. Various numbers of RMA-S and OCM-3 tumor cells were injected either subcutaneously or intracamerally into C57BL/6 severe combined immunodeficiency mice and BALB/c nude mice respectively and tumor growth was monitored. The role of NK cell-mediated cytotoxicity in controlling tumor growth was confirmed by depleting NK cells in severe combined immunodeficiency mice by administering anti-asialo GM1 antibodies before subcutaneous tumor injection. RESULTS: AH significantly inhibited NK cell-mediated lysis of RMA-S and OCM-3 tumor cells in vitro and in vivo. NK sensitive RMA-S (1 x 10(4) cells) and OCM-3 tumors (1 x 10(6), 5 x 10(6) cells) were rejected after subcutaneous injection in C57BL/6 mice, whereas the same or even lower numbers of cells grew progressively in the eye. In vivo NK cell depletion resulted in progressive growth of subcutaneously injected RMA-S tumors at a dose rejected by mice with normal NK cell activity. CONCLUSIONS: AH inhibits NK cell activity in vitro and within the interior of the eye and prevents the rejection of NK-sensitive intraocular tumors.

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PubMed1996

Synthesis and growth inhibitory properties of glycosides of 1-O-hexadecyl-2-O-methyl-sn-glycerol, analogs of the antitumor ether lipid ET-18-OCH3 (edelfosine).

Glycosylated antitumor ether lipids (GAELs), analogs of 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (1, ET-18-OCH3, edelfosine), were synthesized in good overall yields by glycosylation of 1-O-alkyl-2-O-methyl-sn-glycerol and tested for in vitro antineoplastic activity against a variety of murine and human tumor cell lines. Stereospecific glycosylation was achieved by the use of 2-O-acetyl-3,4,6-tri-O-benzylglucopyranosyl and -mannopyranosyl trichloroacetimidates as donors, with trimethylsilyl trifluoromethanesulfonate as catalyst in the presence of molecular sieves at -78 degrees C. The GAELs differ from 1 in having the sn-3-phosphocholine residue replaced by one of the following monosaccharide residues: beta- and alpha-2-deoxy-D-arabino-hexopyranosyl, alpha-D-mannopyranosyl, 2-O-methyl-beta-D-glucopyranosyl, and 2-O-methyl-alpha-D-mannopyranosyl. 1-O-Hexadecyl-2-O-methyl-3-O-(2'-deoxy-beta-D-arabino-hexopyranosyl)- sn-glycerol (2) was more effective than 1 in inhibiting the growth of MCF-7 (human breast cancer) and its adriamycin-resistant form MCF-7/adriamycin, and murine Lewis lung cancer cells. 2-Deoxy-beta-D-arabino-hexopyranoside 2 was also an effective growth inhibitor of two drug-resistant leukemic cell lines, P388/Adr and L1210/vmdr.

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PubMed1995

Alloantigens introduced into the anterior chamber of the eye induce systemic suppression of delayed hypersensitivity to third-party alloantigens through "linked recognition".

It has been recognized for over a century that the anterior chamber of the eye is endowed with unique immunological properties that permit the long-term survival of histoincompatible grafts that would otherwise be rejected at extraocular sites. Immune privilege in the anterior chamber of the eye has been attributed, at least in part, to the active down regulation of systemic delayed-type hypersensitivity (DTH) that is induced when antigens are introduced into this ocular compartment. The antigen-specific suppression of systemic DTH that is induced by anterior chamber priming has been termed anterior chamber-associated immune deviation (ACAID) and has been demonstrated with a variety of antigens. The present report summarizes a systematic evaluation of various categories of histocompatibility antigens for their capacity to induce ACAID. The results indicate that ACAID can be induced against a wide variety of alloantigens ranging from a single minor histocompatibility antigen (H-Y) to mismatches involving the entire major histocompatibility complex plus multiple minor histocompatibility loci. Further investigation revealed that it was possible to induce suppression of DTH to third-party alloantigens providing the alloantigens introduced into the anterior chamber were coexpressed with the third-party alloantigens on cells used for extraocular immunizations.

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PubMed1995

Pharmacokinetics and anti-tumor activity of vincristine encapsulated in sterically stabilized liposomes.

Vincristine is used clinically for the treatment of various types of cancer. Recent significant therapeutic improvements obtained by entrapping anthracyclines in sterically stabilized liposomes raised the question whether the therapeutic index of vincristine can be similarly increased by formulation into such long-circulating liposomes. Encapsulation of vincristine in sterically stabilized liposomes (SL-VCR) prolonged the drug's distribution phase plasma half-life in rats from 0.22 to 10.5 hr. There was no significant difference in LD50 (> < or = 2.5 mg/kg, i.v.), but mice given sublethal doses of SL-VCR experienced significantly less weight loss than those given the same dose of free drug. Compared to free drug, SL-VCR was most effective against i.p. or s.c. implanted tumors. However, i.v. tumor inoculation nullified the therapeutic advantage of encapsulation. A single i.v. 2 mg/kg dose of SL-VCR increased the life span of mice bearing i.v. implanted P388 cells by only 44%, while the life span of i.p. P388 implanted mice was increased by 199%. In an s.c. implanted murine colon carcinoma, multiple doses of free drug did little to slow the growth of the tumors, but SL-VCR was able to produce long-term survivors in several dose regimens. These results indicate that prolonged circulation time increases the therapeutic index of VCR entrapped in liposomes against s.c. or i.p. implanted tumors, but does not improve the drug's activity against rapidly growing i.v. disseminated leukemias.

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PubMed1995

Role of splenic B cells in the immune privilege of the anterior chamber of the eye.

The immune privilege of the anterior chamber (AC) of the eye is largely due to the active down-regulation of systemic delayed-type hypersensitivity (DTH) that is evoked when antigens are introduced into this ocular compartment. This antigen-specific suppression of DTH has been termed anterior chamber-associated immune deviation (ACAID) and has been demonstrated with a wide variety of antigens. Previous studies have shown that antigens introduced into the AC are processed by resident antigen-presenting cells which then migrate to the spleen where they transmit a signal that culminates in the generation of regulatory cells that prevent the development of DTH. Although considerable effort has focused on the nature of the ocular phase of ACAID, the role of the spleen has been largely ignored. The present study tested the hypothesis that B cells are the essential cell population responsible for the splenic phase of ACAID. Splenectomy prevented the induction of ACAID; however, introduction of B cell-enriched spleen cells into the AC of splenectomized mice restored the hosts' capacity to develop ACAID. The same effect, however, could not be produced with B cell-depleted spleen cells. B cell depletion of eusplenic mice by chronic administration of anti-mu antiserum prevented the development of ACAID and thus, had the same of effect as splenectomy. The results indicate that an intact B cell population is necessary for the induction of ACAID. These findings also support the hypothesis that antigens arising in the AC and subsequently delivered to spleen are captured by B cells and presented to T cells in a manner that promotes the development of down-regulatory T cells.

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PubMed1995

Anti-leukocyte function-1 antibody treatment prevents the rejection of intraocular regressor tumors and their metastases.

The role of the cell adhesion molecules, LFA-1 and ICAM-1, in intraocular tumor rejection was examined using four different syngeneic intraocular regressor tumors and four different inbred mouse strains. All four tumors undergo T cell-dependent immune rejection in the syngeneic host. Two of the tumors, D5.1G4 melanoma and P91 mastocytoma, undergo rejection by a cytotoxic T lymphocyte-like immune process. The other two tumors, UV5C25 fibrosarcoma and 124E2 melanoma, are rejected by a process that appears to be mediated by delayed-type hypersensitivity. Systemic administration of anti-LFA-1 prevented the rejection of all four categories of tumors. By contrast, similar in vivo treatment with anti-ICAM-1 antibody did not inhibit tumor rejection. The effect of anti-LFA-1 and anti-ICAM-1 antibody treatment on the rejection of metastases arising from intraocular P91 tumors was also examined and found to be highly dependent upon normal LFA-1 function since antibody treatment with anti-LFA-1 prevented the rejection of metastases. Treatment with anti-ICAM-1 antibody alone had no appreciable effect on the rejection of metastases. The results from this study indicate that the expression and function of LFA-1 is crucial for the generation of immune responses to tumor antigens originating within the eye and the expression of tumor immunity within the eye and at distant sites.

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PubMed1993

Therapy of human ovarian carcinoma xenografts using doxorubicin encapsulated in sterically stabilized liposomes.

BACKGROUND: This study compared the therapeutic effects of doxorubicin hydrochloride in saline and in sterically stabilized, long-circulating liposomes composed of hydrogenated soy phosphatidylcholine/cholesterol/polyethylene glycol-distearoyl-phosphatidyl-ethanolamine (Doxil). METHODS: The drug formulations were injected intravenously or intraperitoneally to treat the human ovarian carcinoma HEY, which was implanted subcutaneously or intraperitoneally into mature female Swiss nude mice. RESULTS: The long-circulating liposome formulation was significantly more effective than was the free drug in inhibiting tumor growth and in producing cure. The liposome formulation was significantly less toxic than was the free drug. This is the first demonstration of the therapeutic effectiveness of doxorubicin in sterically stabilized liposomes against human tumor xenografts. CONCLUSIONS: The encapsulation of doxorubicin in long-circulating liposomes significantly enhanced the therapeutic efficacy of the drug against a human ovarian carcinoma.

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PubMed1993

Antitumor effect of taxol-containing liposomes in a taxol-resistant murine tumor model.

Taxol is a promising agent for use in ovarian cancer and other malignancies. One problem associated with taxol is its low aqueous solubility, requiring Cremophor EL (polyethoxylated castor oil) and ethanol as excipients (Diluent 12); these agents cause serious adverse effects. Liposomes containing taxol and phospholipid (in a 1:33 mole ratio, respectively) were prepared from phosphatidylglycerol and phosphatidylcholine in a 1:9 mole ratio. Antitumor effect was evaluated against Colon-26, a taxol-resistant murine tumor. Given as 1, 4, or 9 injections, free taxol given i.v. in Diluent 12 was ineffective at delaying tumor growth at doses < or = 30 mg/kg per injection (the maximum tolerated dose). In contrast, taxol-liposomes were well tolerated at doses greater than or equal to the maximum tolerated dose of free taxol and showed significant tumor growth inhibition at 10-45 mg/kg per injection.

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PubMed1993

Arrest of human lung tumor xenograft growth in severe combined immunodeficient mice using doxorubicin encapsulated in sterically stabilized liposomes.

Incorporation of polyethylene glycol-derivatized phospholipids into liposomes results in carriers that can enhance the therapeutic efficacy of encapsulated drugs by imparting the ability to evade the reticuloendothelial system and remain in the circulation for prolonged periods. In this study, doxorubicin encapsulated in these sterically stabilized liposomes (S-DOX) is shown to completely arrest the growth of human lung tumor xenografts in severe combined immunodeficient (scid) mice. Doxorubicin administered at equivalent doses as free drug or encapsulated into conventional liposomes was ineffective at completely arresting the growth of this human tumor, although a decrease in tumor growth rate compared to untreated controls was observed. Scid mice were found to be significantly more susceptible to the toxic effects of doxorubicin than were immunocompetent C.B-17 control mice, a characteristic that is likely to result from the deficit in DNA repair mechanisms previously identified in scid mice. However, doxorubicin toxicity in scid mice could be minimized while maintaining the antitumor activity of doxorubicin encapsulated in sterically stabilized liposomes by administering the drug in multiple weekly injections at low doses. This report provides the first evidence that antitumor drugs delivered in sterically stabilized liposomes are more effective at arresting the growth of human tumors than are conventional delivery systems. In addition, the scid mouse is presented as a viable model in which to study novel chemotherapeutic approaches to the treatment of human cancer.

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PubMed1993

Therapy of mouse mammary carcinomas with vincristine and doxorubicin encapsulated in sterically stabilized liposomes.

This study tested the therapeutic effects of vincristine sulfate and doxorubicin hydrochloride, each drug in 2 different formulations: (i) as a solution in saline, and (ii) encapsulated in sterically stabilized, long-circulating liposomes composed of hydrogenated soy-phosphatidylcholine/cholesterol/polyethylene-glycerol-disteroyl++ +- phosphatidylethanolamine. The 4 drug preparations were used to treat s.c. implants of the mouse mammary carcinoma MC2. The drugs were given by i.v. injection over 15 to 18 days, starting 3 days after tumor implantation. The single-drug therapeutic effects of vincristine (S-VCR) and doxorubicin (Doxil) in liposomes were compared, and the 2 preparations were also tested in alternate and in simultaneous combinations. These new liposome formulations of vincristine and doxorubicin were significantly more effective than the free drugs in curing the mice. Alternate, semi-weekly injection of both drugs gave the best therapeutic effect. Prolonged circulation time with increased accumulation in tumors are considered likely reasons for the improved therapeutic efficacy of both drugs when encapsulated in these liposomes.

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PubMed1993

Lipid-associated methylpheophorbide-a (hexyl-ether) as a photodynamic agent in tumor-bearing mice.

Liposomes are a potential system for more selective delivery of photosensitizers (PS) to tumors. Pheophorbides are one series of new PS under investigation for use in photodynamic therapy. The pharmacokinetics, anti-tumor response and normal tissue effects of methylpheophorbide-a-(hexyl-ether) (MPH) associated with negatively charged phospholipid vesicles composed of high and low transition temperature lipids were determined in mice. In some preparations monosialoganglioside, which is known to impart long circulation time to liposomes was also included. Normally water-insoluble MPH could be quantitatively incorporated in multilamellar liposomes up to at least 20 mol MPH/mol lipid% for most liposome compositions and sonicated to form clear suspensions. Evidence from electron microscopy and entrapment of aqueous space markers indicated that the particles formed by sonication were not standard liposomes. Anti-tumor responses to light treatment (135 J/cm2, 665 nm argon-dye laser) 24 h after MPH (0.4 mumol/kg) administration were slightly but significantly greater (P < 0.05) for lipid associated MPH compared to MPH solubilized in Tween 80. There were no major differences in tumor uptake and tumor cell photosensitization between lipid or Tween 80 formulations of MPH, whereas, dependent on lipid composition and time after MPH administration, the doses of light required to cause occlusive vascular damage were increased for the lipid formulations. Pharmacokinetic studies showed rapid dissociation between lipids and MPH in vivo. Lipid formulations are useful for solubilizing MPH and may improve the therapeutic effects of this PS.

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PubMed1993

Effect of anti-ganglioside antibodies on the metastatic spread of intraocular melanomas in a nude mouse model of human uveal melanoma.

In vivo and in vitro studies were performed to determine: (a) if human uveal melanoma cells expressed GD2 and GD3 gangliosides; (b) if anti-GD2 monoclonal antibodies would inhibit the propensity of human uveal melanoma cells to localize in the liver following intravenous injection; and (c) if anti-GD2 monoclonal antibody would reduce the spontaneous metastasis of primary intraocular melanomas in nude mice. The results showed that all three of the human uveal melanoma cell lines tested expressed GD2 and GD3 gangliosides in vitro and in vivo. The human uveal melanoma cell lines preferentially localized in the liver and entered the hepatic parenchyma following spontaneous metastasis from the eyes of nude mice. In vivo administration of anti-GD2 monoclonal antibody produced a sharp reduction in the number of uveal melanoma cells that disseminated to the liver following either intravenous injection or by spontaneous metastasis from primary intraocular melanomas. Collectively, the results demonstrate that uveal melanoma cells display a propensity to localize in the liver after entering the bloodstream; however, this localization can be significantly inhibited by in vivo administration of anti-ganglioside antibodies. The expression of GD2 and GD3 surface gangliosides on uveal melanomas and the capacity of anti-ganglioside antibodies to inhibit metastasis formation in mouse models of ocular and cutaneous melanomas raise the possibility of implementing anti-ganglioside antibodies as potential therapeutic agents for the management of uveal melanoma.

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PubMed1993

Lipids covalently bound to keratins of mouse mammary epithelial cells.

Keratin polypeptides obtained from mouse mammary epithelial cells (MMEC) were found to be modified by covalent attachment of lipids. MMEC in primary culture were incubated in 3H-palmitate and treated with 1.5M KCl/1% Triton X-100 to obtain a cytoskeletal (CS) fraction containing primarily keratin and actin filaments. After exhaustive extraction to remove labeled lipids, the CS proteins were separated by gel electrophoresis, and the labeled 46 kD (K18) and 55 kD (K8) keratin polypeptides were excised, subjected to acid hydrolysis and the chloroform-soluble products were resolved on thin layer chromatography. For both keratins, covalently bound lipid included major peaks which co-chromatographed with fatty acid standards. Also, unlabeled lipid resolving with fatty acid standards was found covalently bound to both keratins. The results are discussed in terms of keratin-lipid-membrane interactions.

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PubMed1993

Novel Taxol formulations: Taxol-containing liposomes.

Taxol is a complex diterpenoid natural product under investigation for therapy of colon, ovarian, lung, and breast cancer, as well as for melanoma and lymphoma. One problem associated with the administration of Taxol is its low solubility; the formulation used clinically contains polyethoxylated castor oil (Cremophor EL) and ethanol as excipients. Cremophor EL is implicated in hypersensitivity reactions observed on infusion of Taxol. To eliminate the Cremophor EL vehicle and possibly improve the antitumor efficacy of Taxol, a systematic approach was taken to formulate Taxol in phospholipid suspensions (liposomes). Prototype formulations were developed that have sufficient chemical and physical stability to test the hypothesis that liposomes can alter the pharmacology of Taxol, in addition to providing a biologically compatible carrier in which to administer the drug. In vitro. Taxol liposomes retain the growth-inhibitory activity of free Taxol against a variety of tumor cell lines. In vivo, preliminary results showed no effect of free Taxol (in Cremophor EL) on the growth of Colon-26, a Taxol-resistant murine tumor, when given at doses that included or exceeded the maximum tolerated dose (MTD). In contrast, Taxol liposomes delayed tumor progression at a dose that exceeded the MTD of free Taxol.

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PubMed1993

'Subthreshold stimulation' of allospecific delayed hypersensitivity by corneal allografts.

Corneal allografts contain few or no Ia+ Langerhans' cells and consistently fail to elicit allospecific delayed-type hypersensitivity (DTH). The present study examined the hypothesis that the inability of corneal allografts to induce allospecific DTH was the result of active suppression. However, the results indicated that an initial exposure to corneal allografts provided a subthreshold stimulus for the induction of DTH because hosts that received a second pair of corneal grafts 7 days later developed DTH. By contrast, hosts that received all four corneal allografts simultaneously, failed to display DTH to donor alloantigens. Hosts that received a single set of corneal allografts did not display DTH to donor alloantigens, yet their spleen cells were capable of transferring DTH to hosts subsequently stimulated with a single set of corneal grafts. The capacity of Langerhans' cell-free corneal grafts to prime the host so that a second set of corneal grafts stimulated DTH to donor alloantigens was termed 'subthreshold stimulation of DTH'. The ability of sequential sets of corneal grafts to induce DTH was abolished by fixation with 0.2% paraformaldehyde. Surprisingly, the single cell-layered corneal endothelium was found to be the crucial corneal component necessary for the induction of allospecific DTH. This unique spectrum of corneal alloimmunogenicity may contribute to the immunological privilege and high success rate of corneal allografts.

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PubMed1993

UVB irradiation renders corneal allografts tolerogenic for allospecific delayed hypersensitivity responses.

Heterotopic corneal allografts treated with ultraviolet (UV) radiation not only failed to elicit allospecific delayed-type hypersensitivity (DTH) responses in mice but rendered the hosts tolerant to subsequent immunization with normally immunogenic corneal allografts. The immunological tolerance induced by UV-treated grafts was cyclophosphamide sensitive and antigen specific. Adoptive transfer studies revealed that the tolerance to donor alloantigens could be transferred with CD4+, CD8- T cells which suppressed alloimmune DTH responses at the afferent but not the efferent limb. The capacity of UV-treated corneal allografts to induce allospecific tolerance was related to UV irradiation and not simply a result of loss of corneal viability. Formalin-fixed corneal allografts could not produce similar tolerization for DTH responses. Selective debridement of either the corneal epithelium or endothelium revealed that the corneal endothelium was the critical layer necessary for UV-dependent tolerance induction. Furthermore, the initial exposure to UV irradiation must occur through the endothelium and not the epithelium. Thus, the single-cell layered corneal endothelium is the target for the immunomodulatory effects of UV irradiation on corneal allografts.

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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)

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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.

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