Academic literature on the topic 'PBI-1402'

Abstract The goal of this study was to determine the potential of PBI-1402, a compound that was shown to provide radio- and chemoprotection, to ameliorate the myeloablative therapy induced cytopenia and/or accelerate blood cell recovery of myeloablated hosts following autologous bone marrow transplantation in mouse model. Mice were exposed to irradiation and transplanted the following day with 5×105 bone marrow cells from syngeneic donors. Following transplantation, mice were divided into two groups that received two different doses of PBI-1402 orally and a control group that received PBS for 14 days post transplantation. The results showed that PBI-1402 treatment significantly diminished post-transplant erythropenia in a dose dependent manner. Similarly, determination of haemoglobin (Hb) demonstrated a significant attenuation of Hb loss and additionally, significantly accelerated post-transplantation recovery with the highest dose of PBI-1402. A significantly higher number of platelets was observed with the highest dose of PBI-1402. In addition, similar results were obtained with analysis of white blood cell (WBC) recovery. To determine if the observed effect of PBI-1402 treatment on red blood cell cytopenia and Hb recovery is the consequence of increased erythrocyte progenitor response to Epo, we performed an Epo dose response experiment on CFU-E bone marrow samples obtained from treated and control mice at different time points post transplantation. The results indicated that erythroid progenitors from treated and control mice responded similarly to Epo. However, PBI-1402 treated mice contained significantly higher number of CFU-E. Interestingly, analysis of more primitive Sca1+ progenitors revealed a significant increase in the number of Sca1+ cells from the bone marrow of mice treated with PBI-1402 (p < 0.05). These results demonstrate that PBI-1402 treatment significantly reduced irradiation induced erythropenia with concomitant acceleration in erythroid and Hb recovery. Additionally, treatment with PBI-1402 accelerated WBC recovery and platelet recovery and increased more primitive Sca1+ progenitors. PBI-1402 may offer protection from myeloabaltive therapy or accelerate recovery from remaining resident or transplanted stem cells.

Abstract Background: PBI-1402 is a novel orally active low molecular weight synthetic compound with erythropoiesis stimulating activity. Furthermore, a clinical phase I study showed that PBI-1402 induced a significant increase (100%, p < 0.0001, compared to placebo) of relative and absolute reticulocyte count in healthy volunteers after 21 days of oral treatment and was devoid of significant side effects. Outcomes: The objectives of this clinical phase Ib/II trial were to study the safety and tolerability of PBI-1402 and to assess its biological efficacy on hemoglobin (Hb) level and red blood cell (RBC) count in patients with Chemotherapy-Induced Anemia (CIA). Methods: An open label phase Ib/II trial, monitored by a US CRO (Pharm-Olam International), was conducted in patients developing anemia after chemotherapy treatment. Three cohorts of 6 CIA patients received 8 weeks of treatment with PBI-1402 once a day, at different doses, and were monitored every two weeks for safety, tolerability, Hb level, RBC count and blood chemistry. Patients remained on their chemotherapy during PBI-1402 treatment. Results: To date, 12 CIA patients have completed their PBI-1402 treatment. 83% of patients demonstrated a significant increase in RBC (p = 0.015) and 66% in Hb (p = 0.038). Among the responders, the mean Hb increase was 1.1 g/dL (p = 0.0007) from a baseline Hb value of 9.8 g/dL. No patient required a blood transfusion and only one patient had an Hb content below 9 g/dL (8.9 g/dL). PBI-1402 was well tolerated and no significant side effects were observed. Conclusion: PBI-1402, via a mechanism of action distinct from erythropoietin, induced sufficient erythropoiesis to raise the RBC level and Hb in CIA patients. In addition, PBI-1402 is safe and well tolerated. PBI-1402 offers the potential for a novel therapy of the anemia of CIA.

Abstract PBI-1402 is a non-toxic, well-defined low molecular weight synthetic hematopoietic growth stimulant. PBI-1402 promotes the proliferation and maturation of hematopoietic progenitors (myeloid and erythroid populations) yielding a biological efficacy comparable to G-CSF, GM-CSF and EPO in in vitro human bone marrow cell proliferation and colony formation assays. An additive effect is observed when PBI-1402 is combined with G-CSF, GM-CSF and EPO. In human bone marrow colony assay, PBI-1402 enhances the differentiation of pluripotent stem cells: CFU-GEMM, CFU-GM with a predominant effect on BFU-E. Furthermore, PBI-1402 exerts its activity via a different mechanism of action than EPO and stem cell factor (SCF) and at an earlier stage on more immature hematopoietic progenitors. PBI-1402 is targeted as an adjunct to cancer chemo/radiotherapy, bone marrow transplantation and diseases involving neutropenia and anemia.

Abstract Erythropoiesis is regulated by an intricated network of transcription factors and other molecules that mediate differentiation of stem cell progenitors into erythroid lineage. PBI-1402 is a non-toxic, well-defined chemo- and radio-protective orally active small molecule which stimulates erythropoiesis. In vivo studies demonstrate that PBI-1402 has an immunorestorative effect in anemia induced by phenylhydrazine or lethal irradiation. In phenylhydrazine-induced anemia, PBI-1402 treated mice had an increased number of hematopoietic progenitor cells compared to the control mice. This increase was more pronounced in the erythroid lineage (BFU-E and CFU-E). In myeloablated mice that received a syngeneic bone marrow transplant, oral treatment with PBI-1402 resulted in a significant increase in peripheral erythrocyte count and hemoglobin concentration. In conclusion, these results indicate that PBI-1402 plays an important role in the formation of red blood cells. Therefore, PBI-1402 may be useful for the treatment of anemia associated with chemotherapy, radiotherapy, bone marrow transplantation and cancer.

Abstract PBI-1402 is an orally active low molecular weight synthetic compound which is currently in a phase Ib/II clinical trial in patients with anemia associated with cancer and/or chemotherapy. PBI-1402 stimulates the in vitro/ex vivo proliferation and maturation of hematopoietic progenitors (erythroid and myeloid populations) with an activity comparable to EPO. Furthermore, an additive effect is observed in combination with EPO. PBI-1402 enhances the differentiation of pluripotent stem cells: CFU-GEMM, CFU-GM with a predominant effect on BFU-E. Clinical phase I study showed that PBI-1402 is devoid of significant side effects. In addition, the clinical phase I results showed statistical increase (100%, p<0.0001) of relative and absolute reticulocyte count in healthy volunteers after 21 days of oral treatment compared to placebo. Preclinical results demonstrated that PBI-1402 yields an increase in erythrocytes in the systemic circulation. In myeloblated mice that received a syngeneic bone marrow transplant, oral treatment with PBI-1402 resulted in a significant increase in peripheral erythrocyte count, hemoglobin, platelet and bone marrow erythroid progenitor cells. PBI-1402 is targeted as an adjunct to cytotoxic drugs, radiotherapy and bone marrow transplantation for the treatment of anemia.

Une des complications importantes d’un traitement intensif de chimio/radio-thérapie est l’aplasie de la moelle osseuse qui peut persister longtemps même après une greffe de cellules souches. Le PBI-1402 est un petit lipide qui a été associé à la diminution de l’apoptose des neutrophiles induite par des agents cytotoxiques. Nos travaux ont démontré que la culture in vitro de progéniteurs hématopoiétiques humains en présence de PBI-1402 induit une augmentation significative du nombre de progéniteurs érythroides (PEryth) (p<0,05). En évaluant la sensibilité des PEryth à l’érythropoietine (Epo), nous avons démontré que le PBI-1402 n’a pas d’effet sensibilisateur et que les cellules répondent de façon similaire aux cellules contrôles. De plus, la combinaison de l’Epo et du « stem cell factor » avec le PBI-1402 permet de prolonger et d’augmenter l’activation d’ERK1/2 (p<0,05), un important signal mitogène. Cet effet est associé à une inhibition de l’activation de la phosphatase MKP-1 dans les cellules exposées au PBI-1402. Nous démontrons aussi la capacité du PBI-1402 à amplifier la prolifération des PEryth et sa capacité à réduire la durée et l’intensité de l’anémie dans un modèle in vivo murin. Des souris ayant reçu une dose létale d’irradiation et subi une transplantation syngénique de moelle osseuse, ont été traitées oralement avec le PBI-1402 pendant 14 jours. Ces souris démontrent une réduction significative de l’anémie post-transplantation versus les souris contrôle (p<0,05). De plus, la moelle osseuse des souris traitées au PBI-1402 présente un nombre de BFU-E et CFU-E plus élevé comparativement au contrôle. Ces résultats démontrent donc le potentiel du PBI-1402 à réduire l’anémie post-transplantation et accélérer la reconstitution érythroïde.<br>One of the most important complications of intensive radiotherapy or chemotherapy is cytopenia, which can persist for significant amount of time even after stem cell transplantation. PBI-1402, a small lipid, was previously shown to be associated with decreased neutrophil apoptosis caused by cytotoxic agents. Our work has shown that day primary human hematopoietic cell in vitro culture in the presence of PBI-1402 resulted in an increased number of erythroid progenitors (p<0,05). Dose-response experiments evaluating sensitivity to erythropoietin (Epo) of cells exposed to PBI-1402 indicated that PBI-1402 did not have a sensitizing effect and that both treated and control cells respond similarly to Epo. In addition, PBI-1402, used in combination with stem cell factor (SCF) and Epo, enhanced and prolonged ERK1/2 phosphorylation (p<0.05), a signalling pathway important for erythroid progenitor cell proliferation. This effect was associated with a decrease of the phosphatase MKP-1 activation in PBI-1402 exposed cells. This translated into and increased proliferation of erythroid progenitors as well as a reduced duration and level of anemia in an in vivo murine transplantation model. Lethally irradiated mice that received syngeneic stem cell transplantation were treated orally with PBI-1402 for 14 days. These mice demonstrated a significant reduction in post-transplantation anemia in a dose dependent manner compared to control (vehicle)(p<0.05). Moreover, PBI-1402-treated mice harboured significantly higher numbers of BFU-E and CFU-E in bone marrow compared to control (p<0.05). These results demonstrate that PBI-1402 treatment significantly reduced transplantation-induced anemia with concomitant acceleration in erythroid recovery.