piperidines and Soft-Tissue-Neoplasms

Inhibition of ChK1 appears as a promising strategy for selectively potentiate the efficacy of chemotherapeutic agents in G1 checkpoint-defective tumor cells such as those that lack functional p53 protein. The p53 pathway is commonly dysregulated in soft-tissue sarcomas (STS) through mutations affecting TP53 or MDM2 amplification. GDC-0575 is a selective ATP-competitive inhibitor of CHK1.. We have performed a systematic screening of a panel of 10 STS cell lines by combining the treatment of GDC-0575 with chemotherapy. Cell proliferation, cell death and cell cycle analysis were evaluated with high throughput assay. In vivo experiments were carried out by using TP53-mutated and TP53 wild-type patient-derived xenograft models of STS. Clinical activity of GDC-0575 combined with chemotherapy in patients with TP53-mutated and TP53 wild-type STS was also assessed.. We found that GDC-0575 abrogated DNA damage-induced S and G2-M checkpoints, exacerbated DNA double-strand breaks and induced apoptosis in STS cells. Moreover, we observed a synergistic or additive effect of GDC-0575 together with gemcitabine in vitro and in vivo in TP53-proficient but not TP53-deficient sarcoma models. In a phase I study of GDC-0575 in combination with gemcitabine, two patients with metastatic TP53-mutated STS had an exceptional, long-lasting response despite administration of a very low dose of gemcitabine whereas one patient with wild-type TP53 STS had no clinical benefit. Genetic profiling of samples from a patient displaying secondary resistance after 1 year showed loss of one preexisting loss-of-function mutation in the helical domain of DNA2.. We provide the first preclinical and clinical evidence that potentiation of chemotherapy activity with a CHK1 inhibitor is a promising strategy in TP53-deficient STS and deserves further investigation in the phase II setting.

Topics: Animals; Cell Line, Tumor; Checkpoint Kinase 1; Deoxycytidine; Dose-Response Relationship, Drug; Female; Gemcitabine; Genes, p53; Heterografts; Humans; Mice; Mice, Knockout; Mice, Nude; Mutation; Piperidines; Pyridines; Pyrroles; Soft Tissue Neoplasms; Tumor Suppressor Protein p53

Incel (biricodar, VX-710) restores drug sensitivity to P-glycoprotein and multidrug resistance-associated protein-1-expressing cells. This Phase I/II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus doxorubicin in patients with inoperable, locally advanced or metastatic, anthracycline-resistant/refractory, soft tissue sarcoma.. In Phase I, i.v. bolus doxorubicin at 60, 75, or 67.5 mg/m(2) was administered 8 h after initiation of a 72-h continuous i.v. (CIV) infusion of VX-710 (120 mg/m(2)/h) to cohorts of patients to establish a maximum tolerated dose. For efficacy evaluations in Phase II, eligible patients had inoperable, locally advanced or metastatic, anthracycline-resistant/refractory soft tissue sarcoma; < or =225 mg/m(2) cumulative prior doxorubicin; and adequate hematological, liver, and kidney function. Cycles were repeated every 3 weeks.. Fourteen patients were enrolled in Phase I. Myelosuppression was the dose-limiting toxicity with 75 and then 67.5 mg/m(2) doxorubicin, and the maximum tolerated dose was established at 60 mg/m(2) with VX-710, 120 mg/m(2)/h, 72-h CIV. VX-710 had no apparent effect on doxorubicin pharmacokinetics. Twenty-nine patients enrolled in Phase II were treated with VX-710, 120 mg/m(2)/h 72-h CIV, and 60 mg/m(2) doxorubicin. Among 26 evaluable patients, minimal activity was noted among 11 patients with gastrointestinal stromal tumors (GISTs); however, in 15 patients with anthracycline-resistant sarcomas of other histologies, 2 achieved partial responses and 7 patients had disease stabilization with an overall median progression-free interval of 3.4 months.. Anthracycline resistance in GISTs appears to be independent of P-glycoprotein or multidrug resistance-associated protein-1 resistance mechanisms. However, the combination of VX-710 and doxorubicin resulted in objective responses or disease stabilization in patients with strictly defined anthracycline-refractory non-GIST sarcomas, which warrants further evaluation.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Disease Progression; Disease-Free Survival; Doxorubicin; Drug Resistance, Neoplasm; Female; Humans; Male; Middle Aged; Piperidines; Pyridines; Sarcoma; Soft Tissue Neoplasms; Time Factors

A 10-year old Arabian mare had a slow-growing mass on the lower right mandible and required a large partial mandibulectomy.. No abnormalities were detected apart from the mass.. A temporary tracheostomy was performed pre-operatively. Anesthesia was induced with xylazine followed by ketamine and diazepam. For 13 hours, anesthesia was maintained using sevoflurane, dexmedetomidine and remifentanil infusions, with the exception of surgical preparation time. Intra-operatively, ventilation was delivered through the cuffed tracheotomy tube. Heart and respiratory rates, ECG, arterial pressures, inspired and expired gases, pulse oximetry values and body temperature were monitored. Dobutamine and whole blood were necessary, and romifidine was used to control recovery. Post-operatively, phenylbutazone and buprenorphine given systemically and bupivacaine administered through a wound soaker catheter were used to provide analgesia. Head-shaking from buprenorphine was controlled with acepromazine and detomidine once standing after 87 minutes in recovery. For 3 days after surgery, analgesia was provided with butorphanol, phenylbutazone and bupivacaine. The mare recovered well, appeared comfortable and started eating the following day with no signs of ileus.. Seven months later, the mare was doing well.. Sevoflurane, dexmedetomidine and remifentanil infusions were suitable for a long and invasive procedure.

Topics: Anesthetics, Inhalation; Animals; Delayed Emergence from Anesthesia; Dexmedetomidine; Female; Horse Diseases; Horses; Hypnotics and Sedatives; Methyl Ethers; Piperidines; Remifentanil; Sarcoma; Sevoflurane; Soft Tissue Neoplasms

Dysregulation of platelet-derived growth factor receptor (PDGFR) may play a role in feline injection-site sarcoma (ISS) cell growth and viability. Masitinib, a tyrosine kinase inhibitor approved for treatment of canine mast cell tumours, is highly selective for the PDGFR signalling pathway and may offer a new therapeutic approach for this disease. The in vitro effects of masitinib on growth, apoptosis and PDGFR signalling in two novel ISS cell lines were investigated. PDGFR expression was confirmed by Western blot in cell lines derived from a primary ISS tumour (JB) and a corresponding, histologically confirmed ISS lung metastasis (JBLM). Masitinib inhibited cell growth and PDGFR phosphorylation in both cell lines. Higher drug concentrations were required to inhibit growth than to modulate ligand-induced autophosphorylation of PDGFR. These in vitro data suggest that masitinib displays activity against both primary and metastatic ISS cell line and may aid in the clinical management of ISS.

Topics: Animals; Antineoplastic Agents; Benzamides; Cat Diseases; Cats; Cell Line, Tumor; Dose-Response Relationship, Drug; Flow Cytometry; Gene Expression Regulation, Neoplastic; Piperidines; Platelet-Derived Growth Factor; Pyridines; Receptors, Platelet-Derived Growth Factor; Sarcoma; Soft Tissue Neoplasms; Thiazoles; Vaccines, Inactivated