Search PubMed⌕ Search

Biomedical subjects

R L Kradin

Publications and source records attributed to R L Kradin.

At least 37 records · Page 2Linked to original sources
PubMed1992

Expression of monocyte chemoattractant protein 1 mRNA in human idiopathic pulmonary fibrosis.

Macrophages are thought to play an important role in the pathologic changes associated with idiopathic pulmonary fibrosis (IPF). The mechanisms for increased monocyte/macrophage recruitment in IPF are unknown. Monocyte chemoattractant protein 1 (MCP-1) is the predominant monocyte chemoattractant secreted by a variety of different cell types in culture. We examined the expression of MCP-1 mRNA and its protein product in vivo in IPF and non-IPF lung specimens by in situ hybridization and immunocytochemistry. The cell types expressing MCP-1 in vivo were identified by immunostaining with specific antibodies. We demonstrated the expression of MCP-1 mRNA in pulmonary epithelial cells, in monocytes/macrophages, and in vascular endothelial and smooth muscle cells. Lung epithelial cells in patients with IPF strongly expressed MCP-1 mRNA and its protein product. In contrast, epithelial cells in non-IPF specimens did not express MCP-1 mRNA. Macrophages and vascular endothelial and smooth muscle cells were shown to express MCP-1 in both IPF and non-IPF lung specimens. These findings provide a basis for the understanding of the in vivo physiologic processes that mediate monocyte/macrophage recruitment and infiltration in the lung interstitium and the pathologic state contributing to an increased alveolar monocyte/macrophage population and inflammation in IPF.

Arteries↗
PubMed1992

Dominant rearrangements among human tumor-infiltrating lymphocytes. Analysis of T-cells derived from 32 patients with melanoma, lung, and renal cell carcinoma.

Dominant rearrangements of T-cell receptor (TCR) beta-chain genes are reported among tumor-infiltrating lymphocytes (TIL). After interleukin-2 expansion of TIL from renal and lung carcinoma and melanoma biopsy tissues, rearrangements of TCR beta-chain genes were analyzed by Southern blotting. Nongermline restriction fragments, indicating dominant rearrangements, were detected among the TIL from all 6 patients with renal cell carcinoma, 17 of 20 patients with melanoma, and 3 of 6 patients with lung tumors. The restriction-fragment sizes of these dominant rearrangements were heterogeneous among the various patients. Rearrangements into C beta 1 were more common than C beta 2 rearrangements. Phenotypic analyses indicated that dominant rearrangements occurred in both CD4 and CD8 predominant TIL populations. The TIL populations that were extracted were expanded to derive large cell numbers suitable for in vivo transfer in an interleukin-2 and TIL immunotherapy program. The data indicated that the cells delivered to these patients usually were characterized by dominant populations of T-cells with selective TCR gene rearrangements. The significance of selective TCR use requires evaluation of the function and specificity of the TIL comprising these dominant populations both in their native in vivo setting and in the context of therapeutic transfer.

Carcinoma, Bronchogenic↗
PubMed1992

A phase II trial of interleukin-2 and interferon alfa-2a in patients with advanced renal cell carcinoma.

PURPOSE: A phase II trial that used a regimen of interleukin-2 (IL-2) and interferon alfa-2a (IFN-alpha) was undertaken to evaluate the efficacy of this combination in the treatment of metastatic renal cell carcinoma. PATIENTS AND METHODS: Thirty-four assessable patients were treated with one to two induction cycles of IL-2 administered by continuous intravenous (IV) infusion at a dose of 3 x 10(6) U/m2/d [corrected] for 4 days per week plus IFN-alpha administered by subcutaneous injection at a dose of 5 x 10(6) U/m2/d [corrected] for 4 days per week for 3 consecutive weeks. A maintenance regimen of IL-2 2 x 10(6) U/m2/d [corrected] given by continuous IV infusion for 5 days per week plus IFN-alpha subcutaneously at a dose of 6 x 10(6) U/m2/d [corrected] that was given 3 days per week for 3 weeks was administered for one to five cycles. Twenty-eight patients (82%) completed one to two induction cycles, and 14 patients (41%) received maintenance doses. RESULTS: Major responses were achieved in four patients (12%), which included one complete response (CR) in a bone metastasis. Responses were observed in patients both with and without prior nephrectomy as well as in a primary tumor. Toxicity was moderately severe and included two treatment-related deaths. CONCLUSIONS: In view of the minimal antitumor activity and associated toxicity, the combination of IL-2 and IFN-alpha in this trial cannot be recommended. The investigation of new cytokines and the identification of biologic prognostic factors for a response to immunologic therapy are essential.

Adult↗
PubMed1991

Cytokine administration alters the distribution of activated lymphocytes to the lung.

The effects of intraperitoneal injections of recombinant interleukin-1 alpha (IL-1; 250,000 U/day), interleukin-2 (IL-2; 50,000 units/day), interferon-gamma (IFN-gamma; 50,000 U/day) and tumor necrosis factor-alpha (TNF; 100,000 U/day), on the biodistribution of concanavalin A (Con A)-activated, indium-111-labeled lymphocytes were evaluated in BALB/c mice. Syngeneic spleen cells were activated for 48 h in medium with Con A (5 micrograms/ml) and maintained in culture for 72 h in IL-2 (1,000 U/ml). Groups of 12 mice were treated for 4 days with either one of the cytokines or saline. On day 4, mice received 10(7) lymphocytes (3-5 mu Ci) intravenously. Mice were sacrificed at 4 and 24 h following injection and the percent of administered dose per organ was determined. TNF and IL-1 produced a significant increase in lung uptake of radiolabeled lymphocytes at 4 and 24 h, whereas IL-2 and IFN-gamma decreased uptake at both time points. IL-1 increased uptake by liver at 4 and 24 h while IL-2 increased uptake only at 4 h. We conclude that the distribution of activated lymphocytes following adoptive transfer is altered by cytokines. This finding may have important implications for cell delivery during adoptive immunotherapy.

Animals↗
PubMed1991

Accessory cells of the lung. I. Interferon-gamma increases Ia+ dendritic cells in the lung without augmenting their accessory activities.

Dendritic cells are specifically adapted to provide accessory signals for the growth of T lymphocytes. Ia+ dendritic cells are present within the normal lung; however, little is known concerning their regulation in vivo. Interferon-gamma (IFN-gamma) is a proinflammatory lymphokine that augments the expression of Ia antigens and promotes the accessory activities of a variety of cells. In order to determine whether IFN-gamma regulates pulmonary dendritic cells in vivo, Lewis rats were injected intraperitoneally with recombinant murine IFN-gamma (2 x 10(5) U/rat/day) or with buffered saline for 5 consecutive days. Following sacrifice, the lungs were excised, and the distribution and number of Ia (OX-6)+ cells was determined in situ. Dendritic cells were localized in the mucosal lining of the tracheobronchial tree, in pulmonary capillaries, as well as in the alveolar septal interstitium and subjacent to the pleural surfaces. IFN-gamma yielded a specific increase in Ia+ dendritic cells in alveolar septa and in pulmonary airways. Purified Ia+ dendritic cells from enzymatic digests of lung were excellent accessory cells for the proliferative responses of both antigen-primed and naive T lymphocytes. IFN-gamma did not, however, further augment the expression of Ia antigens or the accessory activities of pulmonary dendritic cells. These results suggest that IFN-gamma may promote pulmonary T cell-mediated inflammatory responses in vivo by increasing the number of Ia+ dendritic accessory cells in the lung.

Animals↗
PubMed1991

Accessory cells of the lung. II. Ia+ pulmonary dendritic cells display cell surface antigen heterogeneity.

In earlier studies, we had determined that class II (Ia) major histocompatibility complex (MHC) antigen expression in the normal rat lung was limited to dendritic cells and type II alveolar cells. In order to characterize the Ia+ pulmonary dendritic cells of the lung parenchyma, Lewis rat lungs were dissected free of their major airways, enzymatically digested, and serially subjected to density centrifugation on bovine serum albumin, overnight adherence, and immunopanning with a murine anti-rat monoclonal antibody (anti-OX-6) that reacts specifically with class II (Ia) MHC antigens. The purified Ia+ pulmonary cells displayed the morphologic and functional features of dendritic accessory cells, including extended cell processes, absence of nonspecific esterase staining, minimal phagocytosis of latex beads, rapid clustering with T lymphocytes, and co-stimulation of T-cell mitogen responses. Detailed immunophenotyping by cytofluorimetry and immunohistology showed that the purified dendritic cells were Ia (OX-6)+, CD45R (OX-1)+, CD45Rb (OX-22)-, ICAM-1+, and OX-43-. As many as 50% of the cells bound heat-aggregated IgG, while a smaller percentage expressed the CD43 sialophorin antigens (W3/13) expressed by a variety of blood-derived cells, and/or the OX-41 and RMA macrophage antigens. We conclude that Ia+ dendritic cells of lung are heterogeneous with respect to their expression of surface membrane differentiation antigens and may prove to be functionally distinct with respect to their accessory activities.

Animals↗
PubMed1991

Most human pulmonary infiltrating lymphocytes display the surface immune phenotype and functional responses of sensitized T cells.

Pulmonary infiltrating lymphocytes (PIL) isolated directly from human lung were examined for their surface immune phenotype by monoclonal antibody staining and cytofluorimetry. In order to purify PIL, resected lungs were enzymatically digested with collagenase and DNase and subjected to density centrifugation and nylon-wool column separation. In some cases, CD4+ lymphocytes were further purified with alpha CD8 and complement. The majority of pulmonary lymphocytes were CD2+ (87 +/- 1%) and CD3+ (73 +/- 4%). Virtually all of the CD3+ PIL were Ti alpha beta+. Greater than 90% of both CD4+ or CD8+ PIL were CD45RO+ and CD45RA-, consistent with prior antigen sensitization in vivo. A subset of CD4+ PIL (34 +/- 4%) expressed Leu8, the human congener of the murine MEL-14 lymphocyte homing receptor, whereas most homologous CD4+ peripheral blood lymphocytes were Leu8+ (75 +/- 8; P less than 0.01). HLA-DR surface antigens were expressed by 45 +/- 5% of CD4+ PIL versus 9 +/- 1% of CD4+ peripheral blood lymphocytes (P less than 0.001). There was no significant difference in the percentage of low-affinity interleukin-2 (IL-2) receptor-positive CD4+ lymphocytes in lung and blood (9 +/- 3% versus 13 +/- 2%). Analysis of the DNA synthetic cell cycle showed that approximately 5% of blood CD4+ lymphocytes and approximately 25% of CD4+ PIL were in S/G2/M. Compared to homologous blood T cells, purified PIL displayed enhanced proliferative responses to IL-2 and diminished responses to the lectin phytohemagglutinin. Lectin-stimulated PIL showed greater secretion of interferon-gamma and IL-2 than did blood lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1990

Alterations in pulmonary function in cancer patients receiving adoptive immunotherapy with tumor-infiltrating lymphocytes and interleukin-2.

Adoptive immunotherapy with tumor-infiltrating lymphocytes (TIL) and interleukin-2 (IL-2) is currently being investigated in the treatment of chemoresistant cancers. In protocols using high dosages of IL-2 and adoptive transfers of lymphokine-activated killer (LAK) cells, severe pulmonary toxicities, including pulmonary edema and respiratory failure, are regularly observed. Serial measurements of pulmonary function in patients receiving TIL and continuous infusions of moderate dosages of IL-2 showed the development of mild obstructive and restrictive defects. Partial reversibility of the FEV1 with bronchodilators was observed, suggesting the development of hyperreactive airways. Decreases in lung volumes, DLCO, and gas exchange occurred and may reflect pulmonary infiltration by inflammatory cells, increased lung water, or diminished chest wall function. We conclude that adoptive immunotherapy with TIL and IL-2 produces changes in systemic immune response that may contribute to abnormal pulmonary physiology.

Combined Modality Therapy↗
PubMed1989

Characterization of the CD4+ and CD8+ tumor infiltrating lymphocytes propagated with bispecific monoclonal antibodies.

To study the CD4+ and CD8+ tumor infiltrating lymphocytes (TIL) in the antitumor response, we propagated these subsets directly from tumor tissues with anti-CD3:anti-CD8 (CD3,8) and anti-CD3:anti-CD4 (CD3,4) bispecific mAb (BSMAB). CD3,8 BSMAB cause selective cytolysis of CD8+ lymphocytes by bridging the CD8 molecules of target lymphocytes to the CD3 molecular complex of cytolytic T lymphocytes with concurrent activation and proliferation of residual CD3+CD4+ T lymphocytes. Similarly, CD3,4 BSMAB cause selective lysis of CD4+ lymphocytes whereas concurrently activating the residual CD3+CD8+ T cells. Small tumor fragments from four malignant melanoma and three renal cell carcinoma patients were cultured in medium containing CD3,8 + IL-2, CD3,4 + IL-2, or IL-2 alone. CD3,8 led to selective propagation of the CD4+ TIL whereas CD3,4 led to selective propagation of the CD8+ TIL from each of the tumors. The phenotypes of the TIL subset cultures were generally stable when assayed over a 1 to 3 months period and after further expansion with anti-CD3 mAb or lectins. Specific 51Cr release of labeled target cells that were bridged to the CD3 molecular complexes of TIL suggested that both CD4+ and CD8+ TIL cultures have the capacity of mediating cytolysis via their Ti/CD3 TCR complexes. In addition, both CD4+ and CD8+ TIL cultures from most patients caused substantial (greater than 20%) lysis of the NK-sensitive K562 cell line. The majority of CD4+ but not CD8+ TIL cultures also produced substantial lysis of the NK-resistant Daudi cell line. Lysis of the autologous tumor by the TIL subsets was assessed in two patients with malignant melanoma. The CD8+ TIL from one tumor demonstrated cytotoxic activity against the autologous tumor but negligible lysis of allogeneic melanoma targets. In conclusion, immunocompetent CD4+ and CD8+ TIL subsets can be isolated and expanded directly from small tumor fragments of malignant melanoma and renal cell carcinoma using BSMAB. The resultant TIL subsets can be further expanded for detailed studies or for adoptive immunotherapy.

Antibodies, Monoclonal↗
PubMed1989

Identification of pre-T cells in human peripheral blood. Extrathymic differentiation of CD7+CD3- cells into CD3+ gamma/delta+ or alpha/beta+ T cells.

CD7+CD3- cells purified (greater than 99.99%) by FACS from the peripheral blood of healthy adults include precursors for mature T cells that have the capacity to differentiate into TCR-1+ or TCR-2+ CD3+ cells. Extrathymic differentiation was demonstrable from all eight healthy donors in the presence of a high concentration of IL-2, mitogenic levels of PHA, and irradiated blood mononuclear feeder cells, after a lag of approximately 40 d in vitro. The extrathymic T (ET) cells were predominantly TCR-1+, although TCR-2+ cells were also derived. ET TCR-1+ cells were CD4-CD8-, CD4-CD8DIM+, and CD4+CD8-, and were distinguished from natural T TCR-2+ cells by a variety of cell surface markers. The ET cells had phenotypes generally displayed by normal mature T cells, although the CD5DIM+ on ET cells was more typical of thymocytes. Acquisition of CD3 on purified CD7+CD3- cells was not due to antigenic modulation or growth of contaminants, and ET cells could be demonstrated at the clonal level. Studies in athymic mice and bone marrow recipients support the view that extrathymic maturation does occur in vivo. Whether the CD7+CD3- cell population was unexposed to the thymus, or exposed but not processed, is unknown. In any case, unusual or "forbidden" autoreactive specificities are predicted since ET cells differentiate without thymic selection of the TCR.

Antigens, CD7↗
PubMed1989

Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer.

Tumour-infiltrating lymphocytes (TIL) were isolated and expanded from small tumour biopsy samples of twenty-eight patients (thirteen with malignant melanoma, seven with renal cell carcinoma, and eight with non-small-cell lung cancer). The patients were treated with autologous expanded TIL (about 10(10)) and continuous infusions of recombinant human interleukin-2(1-3 x 10(6) U/m2 per 24 h). 29% of the patients with renal cell cancer and 23% of those with melanoma achieved objective tumour responses lasting 3-14 months. Toxic side-effects were limited, and no patient required intensive-care monitoring. Adoptive immunotherapy with TIL and interleukin-2 may be an effective systemic approach to the treatment of some patients with malignant melanoma and renal cell carcinoma.

Carcinoma, Renal Cell↗
PubMed1989

Adoptive immunotherapy with IL-2 results in the loss of delayed-type hypersensitivity responses and the development of immediate hypersensitivity to recall antigens.

Skin testing represents a direct method of assessing immune responses in vivo. Twenty-six patients with metastatic cancer of the lung, kidney, or melanoma were treated with adoptive transfers of autologous tumor-infiltrating or blood lymphocytes and continuous infusions of interleukin-2 (IL-2). Prior to therapy, cutaneous anergy to recall antigens was observed in 19 patients (73%), whereas 6 (27%) displayed normal delayed-type hypersensitivity (DTH) responses. When tested again at the end of therapy, DTH responses could not be elicited in any of the patients. Proliferative responses to skin test antigens, lectins, and IL-2 diminished progressively during therapy but returned to baseline values at 1 month. Unexpectedly, 14 of these patients (53%) developed immediate skin test responses to candida antigens and 5 (19%) to mumps antigens. These immediate responses were characterized by local erythema and induration that developed within minutes of injecting antigen. Biopsies displayed marked dermal edema and infiltration by eosinophils. Although serum IgE levels were not increased, immediate reactivity could be transferred by a heat-sensitive serum factor. The implications of this novel response are uncertain, and its development did not correlate directly with the anti-tumor effects of therapy. We conclude that adoptive immunotherapy with IL-2 produces a reduction in cutaneous DTH and diminished responses to mitogens while simultaneously promoting cutaneous allergy. We hypothesize that this may reflect diminished IL-2 production by antigen-specific helper T cells and that other lymphokines may promote these immediate hypersensitivity responses.

Antigens, Fungal↗
PubMed1989

Acute and chronic hypoxic pulmonary hypertension in guinea pigs.

To determine whether the strength of acute hypoxic vasoconstriction predicts the magnitude of chronic hypoxic pulmonary hypertension, we performed serial studies on guinea pigs. Unanesthetized, chronically catheterized guinea pigs increased mean pulmonary arterial pressure (PAP) from 11 +/- 0.5 to 13 +/- 0.7 Torr in acute hypoxia (10% O2 for 65 min). The response was maximal at 5 min, remained stable for 1 h, and was reversible on return to room air. Cardiac index did not change with acute hypoxia or recovery. Guinea pigs exposed to chronic hypoxia increased PAP, measured in room air 1 h after removal from the hypoxic chamber, to 18 +/- 1 Torr by 5 days with little further increase in PAP to 20 +/- 1 Torr after 21 days. Cardiac index fell from 273 +/- 12 to 206 +/- 7 ml.kg-1.min-1 (P less than 0.05) after 21 days of hypoxia. Medial thickness of pulmonary arteries adjacent to terminal bronchioles and alveolar ducts increased significantly by 10 days. The magnitude of the pulmonary vasoconstriction to acute hypoxia persisted and was unabated during the development and apparent stabilization of chronic hypoxic pulmonary hypertension, suggesting that if vasoconstriction is the stimulus for remodeling, then the importance of the stimulus lessens with duration of hypoxia. In individual animals followed serially, we found no correlation between the magnitude of the acute vasoconstrictor response before chronic hypoxia and the severity of chronic pulmonary hypertension that subsequently developed either because the initial response was small and variable or because vasoconstriction may not be the sole stimulus for vascular remodeling in the guinea pig.

Acute Disease↗
PubMed1989

Antigen-independent binding of T-cells by dendritic cells and alveolar macrophages in the rat.

The antigen-independent binding of CD4+ T-lymphoblasts by alveolar and peritoneal macrophages and splenic dendritic cells (DC) was compared. DC formed clusters with T-lymphoblasts within 30 min at 37 degrees C, whereas alveolar and peritoneal macrophages did not. Antigen-independent binding developed between macrophages and CD4+ blasts by 4 h at 37 degrees C. Binding by alveolar macrophages was trypsin sensitive, magnesium dependent, serum independent, and cold insensitive, whereas binding by DC required serum and was inhibited by cold. Cluster formation (cell aggregates greater than 250 microns 2) by macrophages and CD4+ blasts was increased by interferon-gamma and phorbol esters, but diminished by lipopolysaccharide. However, each of these factors increased cluster formation by blasts with DC. Efforts to promote antigen-independent binding of T cells by Ia+ macrophages did not alter their poor accessory cell capacities. The role of cluster formation in accessory cell activities was examined. Inhibitors of DC clustering, including trypsin, paraformaldehyde, and tunicamycin, abrogated the ability of DC to support antigen presentation and lectin-mediated proliferation. It is concluded that rapid antigen-independent binding to T-cells is a distinct property that is restricted to DC. Exposure to LPS may down regulate nonproductive binding of T-cells to alveolar macrophages. Our data further suggest that accessory cell activities in the rat are not a function of alveolar macrophages and may be limited to specialized Ia+ cells of dendritic lineage.

Animals↗
PubMed1989

Adoptive immunotherapy of murine pulmonary metastases with interleukin 2 and interferon-gamma.

We examined the activities of activated lymphocytes, interferon-gamma (IFN-gamma), and interleukin 2 (IL-2) in adoptive immunotherapy of pulmonary metastases. Pulmonary metastases produced in Balb/c mice by a single tail-vein injection of 5 X 10(5) murine sarcoma (MCB8) tumor cells on day 0 were treated with combinations of Con A-activated lymphocytes (CAL) (3 X 10(7) cells on days 3 and 7), IL-2 (5 X 10(4) U three times a day on days 3 to 8), and IFN-gamma (5 X 10(4) U/mouse on days 1 to 8). Treated tumors contained increased numbers of infiltrating Thy-1.2+ lymphocytes and a predominance of L3T4+(CD4+) lymphocytes. The level of expression of class I and class II MHC antigens by tumor cells in the lung was increased after treatment. Mice that received CAL + IL-2 + IFN-gamma showed approximately 80% reduction in tumor burden as compared to controls (P = 0.001). Mice treated with IL-2 + CAL, or IL-2 + IFN-gamma, displayed approximately 50% reduction (both P less than 0.02 as compared to triple therapy), whereas IL-2, IFN-gamma, or CAL administered as single agents had little effect on pulmonary metastases. We conclude that adoptive immunotherapy with activated lymphocytes and IL-2 is enhanced by IFN-gamma.

Animals↗
PubMed1989

Efficacy of adjuvant interleukin-2 after excision of BALB/c fibrosarcomas.

Interleukin-2 (IL-2) has been evaluated as a therapeutic agent in a number of metastatic tumor systems. We hypothesized that administration of IL-2 might be more effective as adjuvant therapy in the presence of a greatly diminished tumor burden after tumor excision. In this BALB/c methylcholanthrene-induced sarcoma model, excision of 0.3 to 0.4 gm tumors results in local recurrence rates of 50% to 70%. Administration of human recombinant IL-2 at a dose of 50,000 units three times daily for 5 days to animals with established tumors resulted in 100% mortality. IL-2 administration started at the time of tumor implantation had no effect on tumor growth. Mice receiving adjuvant IL-2 at 50,000 units per dose after surgery had prolonged survival compared with controls (79% vs. 32%, p = 0.007); addition of concanavalin A-activated lymphocytes to IL-2 therapy did not enhance survival over that with IL-2 alone. Therapy with lower doses of adjuvant IL-2 on the same treatment schedule resulted in improved survival at doses as low as 5000 units (86% vs. 51% for controls, p = 0.003). Although the exact mechanism of this therapeutic effect has not been determined, IL-2 may act by a variety of mechanisms, including a decrease in the immunosuppressive effects of anesthesia and surgery, the generation of endogenous IL-2-activated effector cells, and the augmentation of efflux of circulating effector cells from peripheral blood into the site of surgically induced inflammation.

Adjuvants, Immunologic↗
PubMed1987

Rapid growth of human cancer cells in a mouse model with fibrin clot subrenal capsule assay.

Rapid in vivo growth of cultured human cancer or leukemia cells was achieved by implantation into the subrenal capsule of mice. A solid structure, necessary for accurate implantation and measurement of tumor growth in this model, was provided by stepwise addition of fibrinogen and thrombin to the tumor cells, leading to rapid enzymatic formation of a solid tumor-fibrin matrix. Human leukemia and epithelial cancers increased in volume between 6- and 40-fold when measured 6-10 days after implantation into normal or immunosuppressed mice. Immunosuppression of host CD-1 mice was achieved by cyclosporine given daily after tumor implantation, cyclophosphamide given preimplantation combined with cyclosporine, or whole-body irradiation given preimplantation. Confirming the validity of tumor measurements, tumor histology in the immunosuppressed mice revealed cell proliferation, invasion, and neovascularization. Similarly, no artifactual measurement of tumor growth was observed by nonviable cancer cells, implanted after in vitro exposure to a known cytotoxic concentration of thiotepa. This model provides an economical, short-term technique for the in vivo study of human tumor growth, for the evaluation of new cancer therapies, and for in vitro - in vivo drug activity correlations in specific types of human cancer or leukemia cell lines.

Animals↗