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L Oleksowicz

Publications and source records attributed to L Oleksowicz.

30 records · Page 2Linked to original sources
PubMed1995

Adhesive receptors expressed by tumor cells and platelets: novel targets for therapeutic anti-metastatic strategies.

In vitro and in vivo studies have demonstrated that adhesive interactions between tumor cells and platelets may play a central role in the metastatic process. Ultrastructural studies have demonstrated that platelets appear to enhance the development of arrested tumor emboli into a secondary metastatic colony. Platelet adhesive glycoprotein receptors and their immunorelated counterparts expressed by tumor cells participate in tumor-induced platelet aggregation, which may be an early step in the development of a metastatic lesion. Platelet anti-adhesive agents have been demonstrated to reduce metastases in rodent models. Although tumor adhesive glycoproteins have yet to be fully characterized, specific inhibition of their functional sites could constitute a forthcoming strategy for effective inhibition of metastases.

Animals↗
PubMed1994

Effects of interleukin-2 administration on platelet function in cancer patients.

Platelet function in 16 patients with metastatic renal cell carcinoma and melanoma was studied sequentially over the first 96 hr of treatment with moderate and high-dose interleukin-2 (IL-2). During the first 96 hr of therapy, an increased ex vivo platelet maximal aggregation (MA) response to ADP, epinephrine, and arachidonic acid was paralleled by a decrease in the peripheral platelet count. Plasma specimens from patients receiving the moderate dose schedule showed a significant IL-2 induced secretory response of the platelet alpha-granule components beta-thromboglobulin (BTG) and platelet factor 4 (PF4) and the eicosanoid thromboxane B2 (TBX2) as measured by RIA. The increase in TXB2 was highly correlated with MA when analyzed by bivariate regression analysis, whereas the addition of PF4 to TXB2 in a multiple regression analysis further increased their correlation to MA. The observed decrease in peripheral platelet count correlated significantly with MA and PF4 secretion. High-dose IL-2-treated patients showed a statistically significant increase in the percentage of large platelets exceeding 12 fl in diameter and platelet responsiveness to hypotonic shock. These observations suggest that IL-2 therapy results in a reduced peripheral platelet pool, with an increased proportion of the remaining pool of platelets larger, more viable, and activated.

Adult↗
PubMed1994

A distinct coagulopathy associated with interleukin-2 therapy.

We studied the coagulation profiles of 14 patients with advanced malignancies treated with Interleukin-2 (IL-2). A 43% prolongation of the PTT (P < 0.001) and a significant decrease in functional levels of factors II, IX, X, XI, and XII were observed 6 h post IL-2 treatment in comparison to pretreatment values. These parameters normalized within 2-3 d following IL-2 administration. The PT, factors V, VII, VIII, fibrinogen and D-dimer levels were unchanged with IL-2 treatment. This pattern of coagulopathy has not previously been reported.

Blood Coagulation Disorders↗
PubMed1994

Platelet activation induced by interleukin-6: evidence for a mechanism involving arachidonic acid metabolism.

The effect of IL-6 on in vitro platelet function was investigated. Platelet-rich plasma (PRP) incubated with IL-6 showed a dose dependent enhancement of agonist induced maximum aggregation (AIMA) and secretion of thromboxane B2 (TXB2) as measured by RIA, in short term incubations. Dazoxiben (0.2 to 160 microM) pretreated PRP incubated with IL-6 and aggregated with ionophore A23187, showed a dose dependent inhibition of TXB2 secretion concomitant with a dose dependent abrogation of IL-6's enhancement of AIMA. A similar abrogation of AIMA was observed when these experiments were repeated using indomethacin. Further, PRP incubated with IL-6 showed a dose dependent increase in TXB2 and BTG secretion as measured by RIA and an increased incorporation of actin binding protein, talin, and myosin into the cytoskeletal core (triton insoluble residue) as shown by SDS-PAGE. The integrin glycoprotein IIIa (GPIIIa) was also observed to be retained into the cytoskeleton by immunoblot. These results suggest that IL-6 activates platelets in vitro and enhances AIMA via a mechanism involving arachidonic acid metabolism.

Adenosine Diphosphate↗
PubMed1993

Role of interleukin-2 and mononuclear cells in platelet-tumor interactions.

Interleukin-2 (IL-2) has been reported to induce mononuclear cell-dependent platelet perturbations and to reduce the incidence of metastases in rodent models. In this study, MC-1 leukemic cell-induced platelet aggregation was associated with a significant increase in thromboxane B2 (TXB2) secretion, quantified by RIA, but a decrease in leukotriene B4 (LTB-4) secretion compared to incubations of tumor cells alone. Whereas MC-1 cells also activated platelets as observed by a significant increase in scanning electron-microscopic spheroidal forms distributed throughout the platelet pool, increasing concentrations of IL-2-activated peripheral blood mononuclear cells (PBMC), but not IL-2 or PBMC alone, reversed this effect with a reduction in activated spheroidal forms. The addition of IL-2-activated PBMC to MC-1 platelet incubations inhibited platelet-tumor cell adhesion and suppressed MC-1-induced aggregation. In order to investigate the mechanism resulting in inhibition of MC-1-induced platelet aggregation, short-term PRP-MC-1 preparations were incubated with IL-2-activated PBMC and assayed for TXB2 and LTB-4 by RIA. LTB-4 levels were significantly elevated in these preparations while levels of TXB2 were significantly reduced compared with control platelet-rich plasma (PRP)-MC-1 incubations. Our results showed that inhibition of MC-1-induced platelet activation, aggregation and tumor-platelet adhesion by the addition of IL-2-activated PBMC was consequent to a cellular effect of IL-2 on PBMC. These findings may be important in understanding the observed antimetastatic effect of IL-2.

Adult↗
PubMed1991

Alterations of platelet function induced by interleukin-2.

We recently reported that thrombocytopenia and bleeding are often limiting effects of immunotherapy with interleukin-2 (IL-2). In order to understand the mechanisms that lead to this unexpected clinical toxicity, we studied the effects of IL-2 on in vitro platelet function. When platelet aggregation was studied using whole blood (impedance, electrical) aggregometry, inhibition of aggregation was detected within 1 min of the addition of exogenous IL-2 to whole blood. IL-2-induced platelet secretion was quantified by radioimmunoassay (RIA) of PF4, BTG, and TXB2 independent of the addition of an aggregating agonist (ADP). Platelet secretion and inhibition of aggregation were an indirect consequence of a cellular effect of IL-2 on mononuclear cells, since aggregation was normal when whole blood was depleted of mononuclear cells and its reconstitution with autologous mononuclear cells led to a cell concentration-dependent inhibitory effect of aggregation and release of alpha-granule components in the presence of IL-2. In order to understand the mechanism of platelet secretion mediated by IL-2-activated mononuclear cells, we quantified the release of eicosanoid products from cultures of mononuclear cells exposed to IL-2 and found a significant increase in TXB2. Our results indicate that platelet secretion, indirectly initiated by IL-2-activated cells, is followed by inhibition of aggregation. These findings may not only have important implications for the planning of clinical immunotherapy trials with IL-2, but may also provide a novel link for a better understanding of the relationships between the hemostatic and the immune systems.

Blood Platelets↗
PubMed1990

Pulmonary carcinoid presenting as multiple subcutaneous nodules.

A 60-year-old female presented with a one-year history of multiple enlarging tender subcutaneous nodules. Initial biopsy demonstrated a poorly differentiated adenocarcinoma. Mammography showed multiple nodular breast lesions. After the patient failed to respond to tamoxifen, a second biopsy demonstrated a metastatic carcinoid tumor. Further search revealed a single small pulmonary nodule, which on aspiration biopsy proved to be a carcinoid tumor. The patient failed to respond to treatment with streptozotocin and 5'-fluorouracil. Therapy with leucovorin calcium and 5'-fluorouracil then produced a partial response.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Thrombocytopenia during immunotherapy with interleukin-2 by constant infusion.

PURPOSE: To elucidate some of the possible mechanisms that lead to interleukin-2 (IL2)-induced thrombocytopenia. PATIENTS AND METHODS: We evaluated retrospectively the effects of immunotherapy with IL2 in 76 patients with disseminated cancer. The lymphokine was administered by constant infusion, daily for 6 days a week for 4 consecutive weeks. RESULTS: A significant decrease in platelet counts was seen after the first 6 days of therapy in all but two patients: 14 patients experienced grade 2 or 3 toxicity, 21 had grade 1 toxicity, and although the decrease in platelet counts could not be graded as toxicity in the remaining 41 patients, there was an average decrease of 32% from baseline platelet counts in 39 (p less than 0.0001). Thrombocytopenia appeared to be secondary to peripheral platelet destruction, since bone marrow biopsy specimens obtained during thrombocytopenia showed hyperplastic megakaryocytopoiesis. IL2 is inactivated by tubular resorption, and severity of thrombocytopenia was strongly correlated with IL2-induced renal dysfunction (p = 0.0004). Additionally, both renal dysfunction and thrombocytopenia were related to total dose of IL2 and were more pronounced in patients with worse baseline renal function and lower baseline platelet counts. The incidence of thrombocytopenia increased with subsequent IL2 therapy: life-threatening thrombocytopenia (less than 25,000/microL) was seen in nine of 57 patients, five of whom required transfusional platelet support. CONCLUSION: On the basis of preliminary observations, we hypothesize that thrombocytopenia induced by IL2 is caused by accelerated clearance of platelets by the reticuloendothelial system.

Adolescent↗
PubMedDate not supplied

Prognostic significance of platelet immunorelated GPIb expression in breast cancer.

PURPOSE: Prior reports have indicated that adhesive glycoprotein receptors expressed by tumor cells enhance their invasive and metastatic properties. We have recently isolated and characterized a platelet immunorelated GPIb receptor expressed by cultured breast tumor cell lines that participates in initial adhesive events in the metastatic process. Whether expression of this receptor predicts tumor behavior or clinical prognosis remains unknown. PATIENTS AND METHODS: Forty sequential breast tissue specimens were examined for GPIb alpha, GPIb/IX, and alpha IIb beta 3 (GPIIb/IIIa) expression by immunohistochemical staining. Of 35 assessable breast specimens, 20 were invasive ductal carcinomas or lobular invasive carcinomas, six were ductal carcinomas in situ (DCIS), and the remaining nine consisted of nonmalignant pathologies. RESULTS: The expression of an immunorelated GPIb alpha and GPIb/IX complex by invasive mammary carcinoma specimens was highly significant (P < 0.0001). However, there was no correlation between alpha IIb beta 3 expression and invasive breast cancer. A GPIb alpha or GPIb/IX staining score of < or = 2.0 and > 2.0 correlated highly with the diagnosis DCIS and invasive carcinoma, respectively (P < 0.0039). Invasive breast carcinoma specimens demonstrated a 120% (P < 0.001) and 140% (P < 0.027) increase in GPIb alpha and GPIb/IX staining score in comparison with DCIS specimens. Expression of GPIb alpha and GPIb/IX correlated significantly with a tumor stage of > or = III (P < 0.008), a tumor size of > 3 cm (P < 0.012), involved axillary nodes (P < 0.004), and estrogen receptor negativity (P < 0.008). Finally, a significant correlation was observed between this receptor's expression and the presence of nodal and/or visceral metastases (P < 0.0035). DISCUSSION: These results demonstrate a significant correlation between GPIb expression and breast malignancy. The expression of the GPIb receptor appears to represent an unfavorable prognostic factor and a biomarker predictive of aggressive disease.

Adult↗