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Results for “SCID mouse”

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At least 541 records · Page 30Linked to original sources

PubMed1994

Successful heterotransplantation of human endometrium in SCID mice.

OBJECTIVE: To establish an experimental system useful for long-term evaluation of human endometrial tissue by its heterotransplantation to SCID mice. METHODS: Human endometrium was transplanted subcutaneously into SCID mice, nude mice, or nude mice given anti-asialo GM1 antibody, a natural killer activity suppressor. The transplant was observed by ultrasonography for up to 10 weeks and then morphologically. To assess the drug susceptibility of the transplant, danazol (10-100 mg/kg/day orally), buserelin (0.01 mg/kg/day subcutaneously), or estradiol (0.5 mg/kg/day intraperitoneally) was administered to the host mice for up to 10 weeks after the transplantation. Multiple-comparison procedures were used for statistical evaluation. RESULTS: The heterotransplant was accepted 100% in SCID mice and natural killer activity-suppressed nude mice, but was significantly inferior (40%) in nude mice at 10 weeks after the transplantation. The transplant size was volumetrically measurable noninvasively by ultrasonography. Using this SCID mouse model, we could evaluate drug effects on the transplanted endometrium. CONCLUSION: This system in SCID mice may be useful for evaluating drug actions on human endometrium and endometriotic tissues.

Adult↗

PubMed1997

Human skin/SCID mouse chimeras as an in vivo model for human cutaneous mast cell hyperplasia.

Human skin xenografted to mice with severe combined immunodeficiency syndrome (SCID) was evaluated to determine the integrity and fate of human dermal mast cells. There was an approximately 3-fold increase in number of dermal mast cells by 3 mo after engraftment (p < 0.05). These cells were responsive to conventional mast cell secretagogues and were confirmed to be of human origin by ultrastructural characterization of granule substructure and by reactivity for the human mast cell proteinase, chymase. CD1a+ Langerhans cells, also bone marrow-derived cells, failed to show evidence of concomitant hyperplasia, and increased mast cell number was not associated with alterations in number of dermal vascular profiles identified immunohistochemically for human CD31. RT-PCR analysis demonstrated human but not murine stem cell factor (SCF; also termed mast cell growth factor, c-kit ligand) mRNA in xenografts. Epidermal reactivity for stem cell factor protein shifted from a cytoplasmic pattern to an intercellular pattern by 3 mo after engraftment, suggesting a secretory phenotype, as previously documented for human cutaneous mastocytosis. The majority (>90%) of mast cells demonstrated membrane reactivity for human SCF at the time points of peak hyperplasia. These data establish SCID mouse recipients of human skin xenografts as a potential in vivo model for cutaneous mast cell hyperplasia.

Animals↗

PubMed1993

An in vivo model of human multidrug-resistant multiple myeloma in SCID mice.

We have established a reproducible in vivo model of human multiple myeloma in the severe combined immunodeficient (SCID) mouse using both the RPMI 8226 human myeloma cell line and the P-glycoprotein-expressing multidrug-resistant 8226/C1N subline. SCID mice 5 to 8 weeks of age were injected intraperitoneally with either 8226 drug-sensitive or P-glycoprotein-expressing multidrug-resistant myeloma cells (8226/C1N). Tumors were detected within 5 days after injection by the presence of human lambda light chain excretion in the mouse urine. Growth of the tumor was observed primarily in the abdominal cavity with spread to the abdominal organs. The anti-neoplastic agent doxorubicin was effective in treating the drug-sensitive 8226 human-SCID xenografts but had no effect on the multi-drug-resistant 8226/C1N human-SCID xenografts. In the 8226-sensitive xenografts, treatment with doxorubicin resulted in a sharp decline in the concentration of human lambda light chain being excreted in the mouse urine. This correlated with an increased survival of the drug-treated animals. This mouse model offers an in vivo means of evaluating efficacy and toxicity of new therapeutic approaches, including development of chemosensitizers directed against P-glycoprotein in multidrug-resistant myelomas.

Animals↗

PubMed2000

Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo.

BACKGROUND AND AIM: Research on hepatitis B virus (HBV) infection in vivo has been limited due to the absence of a suitable animal model. We have developed a human-mouse radiation chimera in which normal mice, preconditioned by lethal total body irradiation and radioprotected with SCID mouse bone marrow cells, are permissive for engraftment of human hematopoietic cells and solid tissues. This resulting human-mouse model, which comprises three genetically disparate sources of tissue, is therefore termed Trimera. This study was aimed at assessing the effect of human IL-6 on HBV infection in vivo in Trimera mice. METHODS: Trimera mice were transplanted with human liver tissue fragments or with HepG2-derived cell lines, which had been previously infected ex vivo with HBV in the presence or absence of human interleukin-6 (hIL-6) and in the presence of anti-IL-6-neutralizing antibodies. RESULTS: HBV sequences appeared in the sera of animals in which the liver tissue was incubated with both HBV and hIL-6 prior to transplantation. A similar result was obtained when a human hepatoblastoma cell line (HepG2), expressing the hIL-6 receptor, was infected ex vivo with HBV in the presence of hIL-6 prior to their injection into spleens of Trimera mice. However, when liver fragments were infected ex vivo and simultaneously treated with neutralizing antibodies against hIL-6 or were incubated with HBV prior to transplantation without hIL-6, the rate of mice positive for HBV DNA in their sera was lower. Human mononuclear cells are also permissive for HBV infection in vitro: in the presence of hIL-6 the infection of these cells is enhanced; and this infection is suppressed by the chimeric protein named Hyper-IL-6, generated by the fusion of hIL-6 to the soluble hIL-6 receptor (sIL-6Ralpha, gp80). CONCLUSION: hIL-6 facilitates HBV infection in vitro and in vivo.

Animals↗

PubMed2005

Activation and antitumor activity of CPT-11 in plasma esterase-deficient mice.

PURPOSE: To examine the antitumor activity and the pharmacokinetics of CPT-11 (irinotecan, 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) in a plasma esterase-deficient scid mouse model, bearing human tumor xenografts. EXPERIMENTAL DESIGN: Plasma carboxylesterase (CE)-deficient mice were bred with scid animals to develop a strain that would allow growth of human tumor xenografts. Following xenotransplantation, the effect of the plasma esterase on antitumor activity following CPT-11 administration was assessed. In addition, detailed pharmacokinetic studies examining plasma and biliary disposition of CPT-11 and its metabolites were performed. RESULTS: In mice lacking plasma carboxylesterase, the mean SN-38 systemic exposures were approximately fourfold less than that observed in control animals. Consistent with the pharmacokinetic data, four to fivefold more CPT-11 was required to induce regressions in human Rh30 xenografts grown in esterase-deficient scid mice, as opposed to those grown in scid animals. Additionally, the route of elimination of CPT-11, SN-38, and SN-38 glucuronide (SN-38G) was principally in the bile. CONCLUSIONS: The pharmacokinetic profile for CPT-11 and its metabolites in the esterase-deficient mice more closely reflects that seen in humans. Hence, these mice may represent a more accurate model for antitumor studies with this drug and other agents metabolized by CEs.

Animals↗

PubMed1992

Development and resolution of Pneumocystis carinii pneumonia in severe combined immunodeficient mice: a morphological study of host inflammatory responses.

The development and resolution of naturally-acquired Pneumocystis carinii pneumonia was studied in a severe combined immunodeficient (SCID) mouse model by light and electron microscopies. Initial infection was evident in 3-week-old SCID mice and started as focal alveolar colonization in the areas near terminal airways. Pronounced pulmonary inflammation occurred in animals of 10 weeks or older and the infection intensity reached a plateau in animals 12 weeks of age. At this stage of disease, the histopathological features of P. carinii infection in SCID mice were similar to those of immunodeficient man. Reconstitution of SCID mice with immunocompetent spleen cells at day 0 induced substantial pulmonary inflammation that was evident already by day 7 and most severe and extensive by day 12. The clearance of P. carinii did not begin until after day 12 and was almost completed by day 17. Alveolar macrophages in mice killed between days 12 and 15, at the time when P. carinii are being rapidly cleared, appeared active but phagocytosis of P. carinii was not commonly observed by either light or electron microscopy. These results suggest that (1) the presence of non-lymphoid inflammatory cells in SCID mice is not sufficient to control P. carinii infection; (2) the clearance of P. carinii from the lungs of reconstituted SCID mice requires local recruitment of large numbers of inflammatory cells with an active appearance; and (3) intracellular killing of P. carinii by phagocytosis does not appear to be a major mechanism in host defences against P. carinii infection in this model.

Age Factors↗

PubMed2002

Selective growth advantage of wild-type lymphocytes in X-linked SCID recipients.

The cytokine receptor common gamma chain (gamma c) plays a pivotal role in multiple interleukin signaling, and gamma c gene mutations cause an X-linked form of SCID (X-SCID). Recently, gamma c gene transfer into the autologous X-SCID BM achieved appreciable lymphocyte reconstitution, contrasting with the limited success in previous gene therapy trials targeting hematopoietic stem cells. To understand the mechanisms underlying this success, we examined the repopulating potential of the wild-type (WT) BM cells using an X-SCID mouse model. Limited numbers of WT cells were infused into non-ablated WT and X-SCID hosts. Whereas no appreciable engraftment was observed in WT recipients, donor-derived lymphocytes repopulated well in X-SCID, reaching 37% (10(6)cells given) and 53% (10(7) cells given) of the normal control value 5 months post BMT. A lineage analysis showed a predominance of the donor-derived lymphocytes (CD4(+) T, CD8(+) T, B and NK cells) in X-SCID while the donor-derived granulocytes and monocytes engrafted poorly. These results showed a selective advantage of WT cells in X-SCID, and that the advantage was restricted to lymphocytes. In human gene therapy for X-SCID, an analogous growth advantage would greatly enhance the repopulation of lymphocytes derived from a very small number of gamma c gene-supplemented precursors.

Animals↗

PubMed1998

Thyrocyte class I and class II upregulation is a secondary phenomenon and does not contribute to the pathogenesis of autoimmune thyroid disease.

It has been proposed elsewhere that thyrocyte (TEC) class I expression plays a central role in the pathogenesis of autoimmune thyroid disease (AITD). We have studied thyroid xenografts from patients with Graves' disease (GD) and normal (paranodular) (N) tissues in nude and severe combined immunodeficient (SCID) mice. TEC class I and II expression are markedly increased in GD, as compared with N thyroids. When these tissues are transplanted to nude mice in which the immune environment is deleted from the thyroid grafts, TEC class I and class II expression decline to low levels; interferon-gamma (IFN-gamma) but not interferon-alpha (IFN-alpha) will then upregulate TEC class I and class II expression in these N and GD nude xenografts. In SCID mouse xenografts, GD tissue shows higher TEC class I and II expression compared with N. In these SCID mice, both IFN-alpha and IFN-gamma will stimulate TEC class I and II expression further in both GD and N. However, only IFN-alpha increases thyroid antibody (TAb) production from GD SCID grafts, whereas IFN-gamma causes a rise in GD TEC class I and II expression, but no significant increase in TAb. Moreover, in N SCID grafts, despite a rise in TEC class I and II expression induced by both IFNs, no TAb could be detected. Because an immune environment is necessary for TEC class I and II upregulated expression, we conclude that such upregulation is a secondary phenomenon. Because there was dissociation between the stimulation of TEC class I and II expression versus the production of TAb, then at least under these experimental conditions, there is no support for a role for TEC class I and class II upregulation in the pathogenesis of AITD.

Animals↗

PubMed1992

Effective immunochemotherapy of CALLA+C mu+ human pre-B acute lymphoblastic leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19) pokeweed antiviral protein immunotoxin plus cyclophosphamide.

A highly aggressive human CALLA+C mu+ pre-B acute lymphoblastic leukemia (ALL) cell line (NALM-6-UM1) causes disseminated and invariably fatal leukemia in CB.17 mice with severe combined immunodeficiency (SCID). We used this SCID mouse model of human pre-B ALL to evaluate and compare, in a total of 434 SCID mice, the antileukemic efficacy of B43 (anti-CD19)-pokeweed antiviral protein (PAP) immunotoxin and cyclophosphamide (CPA) as individual reagents and as combined immunochemotherapeutic regimens. B43-PAP plus CPA was superior to either the immunotoxin or drug alone, and combined immunochemotherapy markedly improved the event-free survival (EFS) of SCID mice challenged with NALM-6-UM1 pre-B ALL cells. Notably, 90% to 100% of SCID mice challenged with 1 x 10(6) leukemia cells and then treated with B43-PAP plus CPA combined immunochemotherapy regimens became long-term survivors, a result not achieved with B43-PAP alone or CPA alone. The advantage was particularly evident in mice inoculated with 5 x 10(6) leukemia cells. While neither 15 micrograms B43-PAP (median survival, 58 days) nor 1 mg CPA (median survival, 49 days) resulted in long-term EFS of SCID mice challenged with 5 x 10(6) NALM-6-UM1 pre-B ALL cells, the probability of EFS at 6 months was 50% +/- 16% for SCID mice treated with 15 micrograms B43-PAP plus 1 mg CPA (median survival, greater than 180 days) (P less than .0001). The probability of long-term EFS was only 14% +/- 7% for mice treated with 30 micrograms B43-PAP and 0% +/- 0% for mice treated with 1 mg CPA, but 40% +/- 16% for mice treated with 30 micrograms B43-PAP plus 1 mg CPA (P less than .0001). Similarly, the probability of EFS at 6 months was 40% +/- 16% for mice treated with 2 mg CPA alone, 70% +/- 15% for mice treated with 2 mg CPA plus 15 micrograms B43-PAP, and 70% +/- 15% for mice treated with 2 mg CPA plus 30 micrograms B43-PAP. Ten SCID mice in the B43-PAP plus CPA combined immunochemotherapy arms surviving long term after the inoculation of 5 x 10(6) NALM-6-UM1 pre-B ALL cells were electively killed at 174 to 181 days to assess their leukemia burden. We found no evidence of leukemia in any of the bone marrow specimens by two-color immunofluorescence and multiparameter flow cytometry.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMedDate not supplied

Cryptosporidial infections in SCID mice reconstituted with human or murine lymphocytes.

Severe combined immunodeficient (SCID) mice were experimentally infected with Cryptosporidium parvum. Adoptive transfer of BALB/c thymocytes, spleen and bone marrow cells resulted in functional immunologic reconstitution followed by complete eradication of the cryptosporidial infection. Additional SCID mice were injected with human blood peripheral blood lymphocytes and were subsequently infected with C. parvum. The latter mice (SCID-hu-PBL) were at least partially reconstituted with human lymphoid tissues, as evidenced by flow cytometric identification of human cell populations in the SCID mouse spleens and the response of these cells to the T-cell mitogen phytohemagglutinin. The SCID-hu-PBL mice did not resolve the cryptosporidial infections, although a transient reduction in parasitemia was noted 4-6 wk post-reconstitution.

Animals↗

PubMed1990

T cell receptor-negative thymocytes from SCID mice can be induced to enter the CD4/CD8 differentiation pathway.

In order to investigate the role of T cell receptor (TcR) expression in thymocyte maturation, we have analyzed thymocytes from C.B-17/SCID mice, which are unable to productively rearrange their antigen receptor genes and fail to express TcR. Despite this defect, SCID thymocytes are functional as they produce lymphokines and proliferate in response to a variety of stimuli. Phenotypic analysis revealed that thymocyte populations from young adult SCID mice resemble thymocyte populations from normal embryonic mice in that they are large, Thy-1.2+, CD4-, CD8-, TcR- and enriched in CD5lo, IL2R+ and Pgp1+ cells. However, other TcR- populations normally present in adult mice (i.e., CD4-CD8+ cells and CD4+CD8+ cells) are absent from the thymus of TcR- adult SCID mice. To understand the basis of the developmental arrest of TcR- SCID thymocytes at the CD4-CD8- stage of differentiation, we analyzed thymi from the occasional "leaky" SCID mouse which possesses small numbers of TcR+ thymocytes. We found that the presence of TcR+ cells within a SCID thymus was invariably associated with the presence of CD4+ and/or CD8+ SCID thymocytes. Interestingly, however, the CD4+/CD8+ SCID thymocytes were not themselves necessarily TcR+. That is, emergence of SCID thymocytes expressing CD4/CD8 was tightly linked to the presence of TcR+ cells within that SCID thymus, but the SCID thymocytes that expressed CD4/CD8 were not necessarily the same cells that expressed TcR. Finally, we found that the introduction into TcR- SCID mice of normal bone marrow cells that give rise to TcR+ cells within the SCID thymus promoted the differentiation of SCID thymocytes into CD4-CD8+ and CD4+CD8+ TcR- cells. These data indicate that TcR+ cells within the thymic milieu provide critical signals which promote entry of CD4-CD8-TcR- precursor T cells into the CD4/CD8 differentiation pathway. When applied to differentiation of normal thymocytes, these findings may imply a critical role for early appearing CD4-CD8- TcR (gamma/delta)+ cells in initiating normal thymic ontogeny.

Animals↗

PubMed1994

T cells and natural killer cells regulate human IgG subclass concentrations in SCID mice.

Cytokine regulation of human IgG subclass production is not well understood. Since T cells and natural killer (NK) cells produce IL-4 and/or IFN-gamma, we examined the effect of these cells on human IgG subclass concentration in reconstituted severe combined immunodeficient (SCID) mice. SCID mice receiving only B-cell-enriched splenocyte preparations had significantly decreased IgG concentrations and significantly decreased IgG1/IgG2 ratios compared to mice receiving B cells plus T cells (P = 0.02). IgG2 represented 58% of the total IgG at 28 days in mice receiving B-cell-enriched preparations compared to 19% of the total for the group receiving both B cells and T cells (P = 0.013). The effect of natural killer cells (CD16+) on IgG subclass was also studied in this model. IgG2 concentrations were twofold higher in mice receiving CD16-depleted cells compared to controls (P = 0.004). No significant differences were noted for IgG1, IgG3, or IgG4 subclass concentrations. In conclusion, T cells and natural killer cells influence human IgG subclass regulation in the SCID mouse model. We propose that the regulation of human IgG subclass production can be further examined in the SCID model.

Animals↗

PubMed1996

T helper cell-dependent, microbial superantigen-mediated B cell activation in vivo.

We have utilized a severe combined immune-deficient (SCID) mouse adoptive transfer model to explore the in vivo immunostimulatory effects of bacterial superantigens (SAg). B cell reconstituted SCID recipients were treated with the Staphylococcus aureus-derived toxic shock syndrome toxin (TSST-1) alone or in conjunction with syngeneic L3T4+ TSST-1-reactive Th cells. Over several months of study, the repetitive administration of TSST-1 resulted in a prompt, transient increase in serum IgG levels. This response required both biologically active TSST-1 and Th cells. These findings demonstrate that certain bacterial SAgs can promote Th cell-dependent B cell activation and differentiation in vivo. These studies strengthen the analogy between SAg-mediated and allospecific Th-B cell interactions responsible for the autoimmune sequelae of graft-versus-host disease.

Animals↗

PubMed2006

Mouse salivary glands and human beta-defensin-2 as a study model for antimicrobial gene therapy: technical considerations.

Transduction of salivary glands with antimicrobial peptide genes has great potential for oral infection control. Our ultimate goal is to introduce antimicrobial peptide genes into salivary glands that secrete these peptides into saliva to control bacterial/fungal infection in the oral cavity. However, an animal study model to test this potential has not been established. Therefore, we determined to test (i) whether the potent antimicrobial peptide human beta-defensin-2 (hBD-2) can be overexpressed in saliva after transduction of salivary glands and (ii) whether oral fungal infection can be developed in a NOD/SCID murine model. Lentiviral vector SIN18cPPTRhMLV bearing hBD-2 cDNA was introduced into SCID mouse submandibular glands via cannulation. Reverse transcription polymerase chain reaction (RT-PCR), immunohistochemistry or enzyme-linked immunosorbent assay (ELISA) were performed to detect hBD-2 expression in glands or in saliva. Candida albicans 613p was inoculated orally into SCID mice to establish oral candidiasis. Whilst expression of hBD-2 was detected in mouse salivary glands by RT-PCR and immunohistochemistry 1 day or 1 week following delivery of lentivirus, hBD-2 was not detected in saliva. There was recoverable C. albicans from the oral cavity and gastrointestinal tract 4 days to 4 weeks after infection, but there was no establishment of observable oral candidiasis in SCID mice under a stereomicroscope. Our data indicate that lentiviral vectors transduce mouse salivary glands, but not at a sufficient level to allow hBD-2 detection in saliva. Other vectors for gene transduction and additional treatment of SCID mice to establish oral candidiasis are needed in order to utilise mouse salivary glands to test antimicrobial gene therapy.

Animals↗

PubMed1998

Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model.

A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer in a human tumor xenograft/ severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.

Animals↗

PubMed2005

Preclinical testing of antileukemic drugs using an in vivo model of systemic disease.

Acute lymphoblastic leukemia (ALL) is predominantly a disease of the bone marrow that disseminates to multiple organ sites throughout the body and, without aggressive treatment, eventually results in multiorgan failure and death. Experimental models that mimic the dissemination of ALL have been difficult to establish, principally due to the poor engraftment efficiency of normal and malignant human hematopoietic cells in various strains of immune-deficient mice. The recent availability of mouse strains that are even more immunocompromised than established strains such as the nude (nu/nu) or severe combined immunodeficient (SCID) mouse has presented opportunities to establish improved experimental models of human leukemia. In this chapter we outline the methodology to (1) establish continuous xenografts from primary childhood ALL biopsies in nonobese diabetic/SCID (NOD/SCID) mice and (2) utilize these xenograft models of systemic disease to test established and experimental drugs while monitoring leukemia progression in "real time" by serial monitoring of murine peripheral blood. These experimental models will be useful for the preclinical evaluation of novel therapies.

Animals↗

PubMed2005

Highly active antiretroviral therapy and human immunodeficiency virus encephalitis.

The ability of highly active antiretroviral therapy (HAART) to prevent the onset of HIV-associated dementia and to prevent or reduce the neuropathological features of HIV encephalitis (HIVE) remains unclear. Using a severe combined immunodeficient (SCID) mouse model of HIVE, we determined the effects of regular HAART treatment on HIVE. Before studying HAART in infected SCID mice, nonmanipulated SCID mice were treated with a single injection of the HAART cocktail (consisting of zidovudine, lamivudine, and indinavir) to determine optimum dosage and sampling time and to measure antiretroviral levels in the brain. After these preliminary studies, SCID mice that were inoculated with either HIV-infected or uninfected human monocytes were given intraperitoneal (IP) injections of HAART three times daily over a 1- and 2-week period. All three drugs were detected in the brain using a novel drug extraction technique and a modified high-performance liquid chromatography method. HAART significantly decreased the amount of astrogliosis and viral load in treated mice compared with mice that received vehicle injections. These studies offer insight into the ability of HAART to treat HIV infection of the brain.

AIDS Dementia Complex↗

PubMed2001

Evaluation of combretastatin A-4 prodrug in a non-Hodgkin's lymphoma xenograft model: preclinical efficacy.

Combretastatin A-4 prodrug (CA4P) is a new antitubulin agent currently in phase I/II clinical trials against solid tumors. We have previously reported on the in vitro activity of CA4P against a panel of malignant human B-lymphoid cell lines. In this study, we investigated the antitumor and the antiangiogenic activity of CA4P in our diffuse large cell lymphoma WSU-DLCL2-SCID mouse model. WSU-DLCL2 cells (10(7)) were injected s.c. into 5-week-old female ICR-SCID mice. Tumor-bearing mice were treated at the CA4P maximum tolerated dose (MTD) of 800 mg/kg in different dose/schedules. CA4P showed significant antitumor activity against this lymphoma model. Best results were seen when MTD was given in two and four divided doses (400 and 200 mg/kg, respectively). CA4P given in four divided doses (4 x 200 mg/kg) showed a log10 kill of 1.01, T/C of 11.7% and T-C of 12 days. Immunohistochemical staining using anti-CD31 antibody after 6, 24, 48 and 120 h treatment revealed a significant decrease in the number of tumor blood vessels after 24 h (about 80%). Only the periphery of treated tumors revealed the presence of blood vessels. Morphological examination of the tumors after tetrachrome staining showed a necrotic center in tumors of CA4P-treated animals. New blood vessel formation was noted to emerge in tumor tissues as early as 48 h following a single dose of CA4P. The G2/M arrest observed in vitro was not detected in vivo indicating predominance of the antiangiogenic effects with regard to antitumor efficacy in vivo. We conclude that CA4P has antiangiogenic activity in this lymphoma model and the use of this agent should be explored clinically in the treatment of non-Hodgkin's lymphoma.

Animals↗