Bcr-Abl inhibition as a modality of CML therapeutics.
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Animals↗
Biomedical subjects
E Buchdunger
Publications and source records attributed to E Buchdunger.
Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis.
Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma (GCF) are recurrent, infiltrative skin tumors that presently are treated with surgery. DFSP and GCF tumors are genetically characterized by chromosomal rearrangements fusing the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor B-chain (PDGFB) gene. It has been shown that the resulting COL1A1/PDGF-B fusion protein is processed to mature PDGF-BB. Autocrine PDGF receptor stimulation has therefore been predicted to contribute to DFSP and GCF tumor development and growth. Here we demonstrate presence of activated PDGF receptors in primary cultures derived from six different DFSP and GCF tumors. Three of the primary cultures were further characterized; their in vitro growth displayed an increased sensitivity to treatment with the PDGF receptor tyrosine kinase inhibitor STI571, as compared with normal fibroblasts. Transplantable tumors, displaying a DFSP-like histology, were established from one of the DFSP primary cultures. Treatment of tumor-bearing severe combined immunodeficient mice with STI571 reduced tumor growth. The growth-inhibitory effects in vitro and in vivo occurred predominantly through induction of tumor cell apoptosis. Our study demonstrates growth-inhibitory effects of PDGF receptor antagonists on human DFSP- and GCF-derived tumor cells and demonstrates that autocrine PDGF receptor stimulation provides antiapoptotic signals contributing to the growth of these cells. These findings suggest targeting of PDGF receptors as a novel treatment strategy for DFSP and GCF.
Adult↗
Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
BACKGROUND: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. METHODS: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. RESULTS: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. CONCLUSIONS: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.
Adult↗
Inhibition of platelet-derived growth factor receptors reduces interstitial hypertension and increases transcapillary transport in tumors.
Most solid malignancies display interstitial hypertension and a poor uptake of anticancer drugs. Platelet-derived growth factor (PDGF) and the cognate tyrosine kinase receptors are expressed in many tumors. Signaling through PDGFbeta receptors was shown recently to increase interstitial fluid pressure (IFP) in dermis after anaphylaxis-induced lowering of IFP. In this study, we show that treatment with the selective PDGF receptor kinase inhibitor, STI571, formerly known as CGP57148B, decreased the interstitial hypertension and increased capillary-to-interstitium transport of 51Cr-EDTA in s.c. growing rat PROb colonic carcinomas. Furthermore, treatment with an antagonistic PDGF-B oligonucleotide aptamer decreased interstitial hypertension in these tumors. PDGFbeta receptors were expressed in blood vessels and stromal cells but not in the tumor cells of PROb colonic carcinomas. Our study indicates a previously unrecognized role of PDGF receptors in tumor biology, although similar effects of PDGF on IFP have been demonstrated previously in the dermis. The data suggest interference with PDGF receptors, or their ligands, as a novel strategy to increase drug uptake and therapeutic effectiveness of cancer chemotherapy.
Animals↗
Tyrosine kinase inhibitors: from rational design to clinical trials.
Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.
Animals↗
Optimization for the blockade of epidermal growth factor receptor signaling for therapy of human pancreatic carcinoma.
We determined the optimal administration schedule of a novel epidermal growth factor receptor (EGFR) protein tyrosine kinase inhibitor (PKI), PKI 166 (4-(R)-phenethylamino-6-(hydroxyl)phenyl-7H-pyrrolo[2.3-d]-pyrimidine), alone or in combination with gemcitabine (administered i.p.) for therapy of L3.6pl human pancreatic carcinoma growing in the pancreas of nude mice. Seven days after orthotopic implantation of L3.6pl cells, the mice received daily oral doses of PKI 166. PKI 166 therapy significantly inhibited phosphorylation of the EGFR without affecting EGFR expression. EGFR phosphorylation was restored 72 h after cessation of therapy. Seven days after orthotopic injection of L3.6pl cells, groups of mice received daily or thrice weekly oral doses of PKI 166 alone or in combination with gemcitabine. Treatment with PKI 166 (daily), PKI 166 (3 times/week), or gemcitabine alone produced a 72%, 69%, or 70% reduction in the volume of pancreatic tumors in mice, respectively. Daily oral PKI 166 or thrice weekly oral PKI 166 in combination with injected gemcitabine produced 97% and 95% decreases in volume of pancreatic cancers and significant inhibition of lymph node and liver metastasis. Daily oral PKI 166 produced a 20% decrease in body weight, whereas treatment 3 times/week did not. Decreased microvessel density, decreased proliferating cell nuclear antigen staining, and increased tumor cell and endothelial cell apoptosis correlated with therapeutic success. Collectively, our results demonstrate that three weekly oral administrations of an EGFR tyrosine kinase inhibitor in combination with gemcitabine are sufficient to significantly inhibit primary and metastatic human pancreatic carcinoma.
Administration, Oral↗
Intracranial inhibition of platelet-derived growth factor-mediated glioblastoma cell growth by an orally active kinase inhibitor of the 2-phenylaminopyrimidine class.
Glioblastoma multiforme is the most common primary human brain tumor, and it is, for all practical purposes, incurable in adult patients. The high mortality rates reflect the fact that glioblastomas are resistant to adjuvant therapies (radiation and chemicals), the mode of action of which is cytotoxic. We show here that an p.o.-active small molecule kinase inhibitor of the 2-phenylaminopyrimidine class may have therapeutic potential for glioblastomas. STI571 inhibits the growth of U343 and U87 human glioblastoma cells that have been injected into the brains of nude mice, but it does not inhibit intracranial growth of ras-transformed cells. Studies on a broad panel of genetically validated human and animal cell lines show that STI571 acts by disruption of the ligand:receptor autocrine loops for platelet-derived growth factor that are a pervasive feature of malignant astrocytoma. The cellular response of glioblastoma cells to STI571 does not appear to involve an apoptotic mechanism.
3T3 Cells↗
New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis
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Journal Article↗
New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis.
The sprouting of new blood vessels, or angiogenesis, is necessary for any solid tumor to grow large enough to cause life-threatening disease. Vascular endothelial growth factor (VEGF) is one of the key promoters of tumor induced angiogenesis. VEGF receptors, the tyrosine kinases Flt-1 and KDR, are expressed on vascular endothelial cells and initiate angiogenesis upon activation by VEGF. 1-Anilino-(4-pyridylmethyl)-phthalazines, such as CGP 79787D (or PTK787 / ZK222584), reversibly inhibit Flt-1 and KDR with IC(50) values < 0.1 microM. CGP 79787D also blocks the VEGF-induced receptor autophosphorylation in CHO cells ectopically expressing the KDR receptor (ED(50) = 34 nM). Modification of the 1-anilino moiety afforded derivatives with higher selectivity for the VEGF receptor tyrosine kinases Flt-1 and KDR compared to the related receptor tyrosine kinases PDGF-R and c-Kit. Since these 1-anilino-(4-pyridylmethyl)phthalazines are orally well absorbed, these compounds qualify for further profiling and as candidates for clinical evaluation.
Administration, Oral↗
Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma.
We determined whether down-regulation of the epidermal growth factor-receptor (EGF-R) signaling pathway by oral administration of a novel EGF-R tyrosine kinase inhibitor (PKI166) alone or in combination with gemcitabine (administered i.p.) can inhibit growth and metastasis of human pancreatic carcinoma cells implanted into the pancreas of nude mice. Therapy beginning 7 days after orthotopic injection of L3.6pl human pancreatic cancer cells reduced the volume of pancreatic tumors by 59% in mice treated with gemcitabine only, by 45% in those treated with PKI166 only, and by 85% in those given both drugs. The combination therapy also significantly inhibited lymph node and liver metastasis, which led to a significant increase in overall survival. EGF-R activation was significantly blocked by therapy with PKI166 and was associated with significant reduction in tumor cell production of VEGF and IL-8, which in turn correlated with a significant decrease in microvessel density and an increase in apoptotic endothelial cells. Collectively, our results demonstrate that oral administration of an EGF-R tyrosine kinase inhibitor decreased growth and metastasis of human pancreatic cancer growing orthotopically in nude mice and increased survival. The therapeutic effects were mediated in part by inhibition of tumor-induced angiogenesis attributable to a decrease in production of proangiogenic molecules by tumor cells and increased apoptosis of tumor-associated endothelial cells.
Administration, Oral↗
Substituted 5,7-diphenyl-pyrrolo[2,3d]pyrimidines: potent inhibitors of the tyrosine kinase c-Src.
5,7-Diphenyl-pyrrolo[2,3d]pyrimidines represent a new class of highly potent inhibitors of the tyrosine kinase c-Src (IC50 < 50 nM) with specificity against a panel of different tyrosine kinases. The substitution pattern on the two phenyl rings determines potency and specificity and provides a means to modulate cellular activity.
Animals↗
PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration.
PTK787/ZK 222584 (1-[4-chloroanilino]-4-[4-pyridylmethyl] phthalazine succinate) is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, such as the platelet-derived growth factor (PDGF) receptor beta tyrosine kinase, c-Kit, and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families, such as epidermal growth factor receptor, fibroblast growth factor receptor-1, c-Met, and Tie-2, or intracellular kinases such as c-Src, c-Abl, and protein kinase C-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of kinase insert domain-containing receptor (KDR), endothelial cell proliferation, migration, and survival in the nanomolar range in cell-based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or antiproliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once-daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown s.c. in nude mice, as well as a murine renal carcinoma and its metastases in a syngeneic, orthotopic model. Histological examination of tumors revealed inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent or impair hematopoetic recovery after concomitant cytotoxic anti-cancer agent challenge. This novel compound has therapeutic potential for the treatment of solid tumors and other diseases where angiogenesis plays an important role.
Angiogenesis Inhibitors↗
The selective tyrosine kinase inhibitor STI571 inhibits small cell lung cancer growth.
At least 70% of small cell lung cancers express the Kit receptor tyrosine kinase and its ligand, stem cell factor (SCF). Numerous lines of evidence have demonstrated that this coexpression constitutes a functional autocrine loop, suggesting that inhibitors of Kit tyrosine kinase activity could have therapeutic efficacy in this disease. STI571, formerly known as CGP 57148B, is a p.o. bioavailable 2-phenylaminopyrimide derivative that was designed as an Abl tyrosine kinase inhibitor, but also has efficacy against the platelet-derived growth factor receptor and Kit in vitro. Pretreatment of the H526 small cell lung cancer (SCLC) cell line with STI571 inhibited SCF-mediated Kit activation with an IC50 of 0.1 microM as measured by inhibition of receptor tyrosine phosphorylation and 0.2 microM as measured by immune complex kinase assay. This paralleled the inhibition of SCF-mediated growth by STI571, which had an IC50 of approximately 0.3 microM. Growth inhibition in SCF-containing medium was accompanied by induction of apoptosis. STI571 efficiently blocked SCF-mediated activation of mitogen-activated protein kinase and Akt, but did not affect insulin-like growth factor-1 or serum-mediated mitogen-activated protein kinase or Akt activation. Growth of five of six SCLC cell lines in medium containing 10% FCS was inhibited by STI571 with an IC50 of approximately 5 microM. Growth inhibition in serum-containing medium appeared to be cytostatic in nature because no increase in apoptosis was observed. Despite this growth inhibition, STI571 failed to enhance the cytotoxicity of either carboplatinum or etoposide when coadministered. However, taken together with the minimal toxicity that this compound has shown in preclinical studies, these data suggest that STI571 could have a role in the treatment of SCLC, possibly to block or slow recurrence after chemotherapy-induced remissions.
Antineoplastic Agents↗
Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-kit and platelet-derived growth factor receptors.
STI571 (formerly known as CGP 57148B) is a protein-tyrosine kinase inhibitor that is currently in clinical trials for the treatment of chronic myelogenous leukemia. STI571 selectively inhibits the Abl and platelet-derived growth factor (PDGF) receptor tyrosine kinases in vitro and blocks cellular proliferation and tumor growth of Bcr-abl- or v-abl-expressing cells. We have further investigated the profile of STI571 against related receptor tyrosine kinases. STI571 was found to potently inhibit the kinase activity of the alpha- and beta-PDGF receptors and the receptor for stem cell factor, but not the closely related c-Fms, Flt-3, Kdr, Flt-1, and Tek tyrosine kinases. Additionally, no inhibition of c-Met or nonreceptor tyrosine kinases such as Src and Jak-2 has been observed. In cell-based assays, STI571 selectively inhibited PDGF and stem cell factor-mediated cellular signaling, including ligand-stimulated receptor autophosphorylation, inositol phosphate formation, and mitogen-activated protein kinase activation and proliferation. These results expand the profile of STI571 and suggest that in addition to chronic myelogenous leukemia, STI571 may have clinical potential in the treatment of diseases that involve abnormal activation of c-Kit or PDGF receptor tyrosine kinases.
Animals↗
The dermatofibrosarcoma protuberans-associated collagen type Ialpha1/platelet-derived growth factor (PDGF) B-chain fusion gene generates a transforming protein that is processed to functional PDGF-BB.
Dermatofibrosarcoma protuberans (DFSP) displays chromosomal rearrangements involving chromosome 17 and 22, which fuse the collagen type Ialpha1 (COLIA1) gene to the platelet-derived growth factor (PDGF) B-chain (PDGFB) gene. To characterize the functional and structural properties of the COLIA1/PDGFB fusion protein, we generated a stable NIH3T3 cell line that contained a tumor-derived chimeric gene resulting from a COIA1 intron 7-PDGFB intron 1 fusion. Expression of the fusion protein led to morphological transformation and increased growth rate of these cells. The PDGF receptor kinase inhibitor CGP57148B reversed the transformed phenotype and reduced the growth rate of COLIA1/PDGFB-expressing cells but had no effects on control cells. The presence of dimeric COLIA1/PDGFB precursors was demonstrated through PDGFB immunoprecipitations of metabolically labeled cells and also by PDGFB immunoprecipitations followed by immunoblotting with COLIA1 antibodies. Pulse-chase studies demonstrated that the COLIA1/PDGFB precursor was processed to an end product that was indistinguishable from wild-type PDGF-BB. Finally, COLIA1/PDGFB-expressing cells generated tumors after s.c. injection into nude mice, and tumor growth was reduced by treatment with CGP57148B. We conclude that the COLIA1/PDGFB fusion associated with DFSP contributes to tumor development through ectopic production of PDGF-BB and the formation of an autocrine loop. Our findings, thus, suggest that PDGF receptors could be a target for pharmacological treatment of DFSP and giant cell fibroblastoma, e.g., through the use of PDGF receptor kinase inhibitors such as CGP57148B.
3T3 Cells↗
Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.
BACKGROUND: Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. METHODS AND RESULTS: The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells. CONCLUSIONS: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.
Animals↗
In vivo eradication of human BCR/ABL-positive leukemia cells with an ABL kinase inhibitor.
BACKGROUND: The leukemia cells of approximately 95% of patients with chronic myeloid leukemia and 30%-50% of adult patients with acute lymphoblastic leukemia express the Bcr/Abl oncoprotein, which is the product of a fusion gene created by a chromosomal translocation [(9:22) (q34;q11)]. This oncoprotein expresses a constitutive tyrosine kinase activity that is crucial for its cellular transforming activity. In this study, we evaluated the antineoplastic activity of CGP57148B, which is a competitive inhibitor of the Bcr/Abl tyrosine kinase. METHODS: Nude mice were given an injection of the Bcr/Abl-positive human leukemia cell lines KU812 or MC3. Tumor-bearing mice were treated intraperitoneally or orally with CGP57148B according to three different schedules. In vitro drug wash-out experiments and in vivo molecular pharmacokinetic experiments were performed to optimize the in vivo treatment schedule. RESULTS: Treatment schedules administering CGP57148B once or twice per day produced some inhibition of tumor growth, but no tumor-bearing mouse was cured. A single administration of CGP57148B caused substantial (>50%) but short-lived (2-5 hours) inhibition of Bcr/Abl kinase activity. On the basis of the results from in vitro wash-out experiments, 20-21 hours was defined as the duration of continuous exposure needed to block cell proliferation and to induce apoptosis in these two leukemia cell lines. A treatment regimen assuring the continuous block of the Bcr/Abl phosphorylating activity that was administered over an 11-day period cured 87%-100% of treated mice. CONCLUSION: These data indicate that the continuous block of the oncogenic tyrosine kinase of Bcr/Abl protein is needed to produce important biologic effects in vivo.
Animals↗