PurposeWe conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies.Patients and ...
PubMed Central
Radiation therapy remains a promising modality for curative treatment of localized prostate cancer, but dose-limiting toxicities significantly limit its effectiveness. Agents that enhance efficacy at lower radiation doses might have considerable value in increasing tumor control without compromising organ function. Here, we tested the hypothesis that the PARP inhibitor ...
PubMed
brca1 Mutation Carrier; brca2 Mutation Carrier; Breast Cancer; Fallopian Tube Cancer; Hereditary Breast/Ovarian Cancer (brca1, brca2); Ovarian Cancer; Pancreatic Cancer; Peritoneal Cavity Cancer; Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific
ClinicalTrials.gov
ABT-888 is a potent, orally bioavailable PARP-1/2 inhibitor shown to potentiate DNA damaging agents. The ability to potentiate temozolomide (TMZ) and develop a biological marker for PARP inhibition was evaluated in vivo. Doses/schedules that achieve TMZ potentiation in the B16F10 syngeneic melanoma model were utilized to develop an ELISA to detect a ...
Breast Cancer; Lymphoma; Lymphoproliferative Disorder; Unspecified Adult Solid Tumor, Protocol Specific
Product Name: ABT-888 Capsules, 10 mg & 50 mg Issued: Jan-23-2007 MATERIAL SAFETY DATA SHEET 1. CHEMICAL PRODUCT AND COMPANY IDENTIFICATION Manufacturer Name and Address: Abbott Laboratories Global Pharmaceutical Research and Development Abbott
Cancer.gov
In this clinical trial, patients with solid tumors or lymphomas that have not responded to previous treatment (refractory cancer), or for which no effective treatment exists, will receive the PARP inhibitor ABT-888 and metronomic cyclophosphamide.
A correlation between radiosensitive and polyploidal behaviors of malignant cells in vivo was assessed in twenty cases of epidermoid carcinomata of the human cervix uteri. It has been observed that in the majority of the cases (75%), there is a correlation between higher ploidy (more than sixty chromosomes) of malignant cells ...
Energy Citations Database
A number of newly synthesized compounds whose chemical structure suggested possible or remotely possible ability to radiosensitize hypoxic mammalian cells were studied in an in-vitro system. Those compounds that were not excluded because of insolubility or extreme cytotoxicity were tested for radiosensitizing ability. The correlation between chemical ...
PURPOSE: To assess the possible radiosensitizing capabilities of two different poly(ADP-ribose) polymerase (PARP) inhibitors in combination with external beam and I-tositumomab in a non-Hodgkin's lymphoma cell line. METHODS AND MATERIALS: Epstein-Barr virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase in log-phase ...
Abbott Laboratories Takebe BCL2 family inhibitor, BH3 mimetic BCL2, BH3 Small Molecule Apoptosis Inducing Agent ABT-888 Abbott Laboratories Chen, A. PARP inhibition induces cytotoxicity in the presence of DNA-damaging agents PARP-1 and PARP-2 inhibitor Small Molecule Chemosensitizer AFP464 (aminoflavone prodrug) Tigris Pharmaceuticals Inc Chen, A.
PurposeABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF ...
A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) ...
A new compound, called ABT-888, has passed the first stage of clinical examination using a new model for drug development that promises to shorten -- by up to six to 12 months -- the timeline for taking anticancer drugs from the laboratory to the clinic, according to a team of researchers at the NCI.
First Phase 0 Oncology Trial Shows Effectiveness of New Drug on Its Target The first phase 0 clinical trial of a drug in cancer treatment, involving 13 patients with advanced cancers, showed that the drug, ABT-888, affected its target and was well tolerated.
A new compound, called ABT-888, has passed the first stage of clinical examination using a new model for drug development that promises to shorten -- by up to six to 12 months -- the timeline for taking anticancer drugs from the laboratory to the clinic, according to a team of researchers at the National Cancer Institute (NCI), part of the National ...
DNA damaging agents are among the most successful treatments for cancer. The enzyme Poly(ADP-ribose)polymerase (abbreviated PARP) can facilitate repair of DNA damage caused by insult from chemotherapeutic agents and radiation. Increased PARP activity is associated with survival of some cancer cells. ABT-888, an orally bioavailable PARP-inhibitor developed ...
Poly(ADP-Ribose) (PAR) polymerase (PARP) inhibitors represent a promising class of novel anticancer agents. The present study explores the molecular rationale for combining veliparib (ABT-888) with camptothecin (CPT) and its clinical derivatives, topotecan and irinotecan. ABT-888 inhibited PAR induction by CPT and ...
Acinic cell carcinomas of the parotid should be considered distinct malignancies despite descriptions of low-grade malignant potential and innocuous histologic patterns. Benign-appearing tumors frequently have a clinically malignant course. Blood-borne metastases may oocur early despite gross and microscopic innocence. Indolent growth ...
Resistance to temozolomide (TMZ) and radiotherapy (RT) is a major problem for patients with GBM but may be overcome using the PARP-inhibitor ABT-888. Using two primary GBM xenografts, the efficacy of ABT-888 combined with RT and/or TMZ was evaluated. Treatment with ABT-888 combined with TMZ resulted in significant survival prolongation (GBM12: 55.1%, ...
A method to render radiosensitive all the cancer cells in the tumor mass is presented. Radiation sensitivity of tumors was shown to be augmented by pretreatment with dicetol. Since dicetol is non-toxic in therapeutic doses it is suggested that combined treatment with dicetol and radi ation may help in increasing the therapeutic effectiveness of radiation therapy in ...
The radioprotection of the rat parotid gland by WR-2721 alone (DMF, 2.4) was compared to the protection afforded when WR-2721 was given in combination with the hypoxic cell radiosensitizer Ro-07-0582 (DMF, 2.6). It was concluded that the radiosensitizer of malignant tumor cells Ro-07-0582 was compatible with and did not reduce the ...
... that ATO may act as a radiosensitizer in cancer therapy (7, 21, 22). ... and may increase the cure rate for malignant gliomas (7, 24). Low doses ... ...
NBII National Biological Information Infrastructure
A report of a maligmant round-cell rhabdomyosarcoma in the masal fossa of a child, with metastases to the cervical lymph nodes, is presented. Both primary and metastatic tumors were extremely radioresponsive but recurred despite thorough irradiation in the treated areas within six months. (auth)
... and Treatment M059K and M059J are two malignant glioma cell lines derived from the same patient tumor sample but with different radiosensitivity and genetic backgrounds. ... ...
A number of investigators have reported the radiosensitizing effects of chlorpromazine (CPZ) in the treatment of malignant melanoma. In the present study, we explored radiosensitization of Fortner's melanoma in the hamster, by use of the 7-hydroxy metabolite (7-OHCPZ) of CPZ. In conjunction with orthovoltage photon radiation ...
Sixty-nine patients with various malignant tumors were treated with different regimens of radiotherapy or chemotherapy combined with HpD. The immediate response showed that the over-all response rate was 94.2% and complete response rate was 60.9%. The present study suggests that HpD be used as a radiosensitizer with mild side effects but no drug resistance ...
NASA Astrophysics Data System (ADS)
The authors reported previously that human cells after neoplastic transformation in culture had acquired an increased susceptibility to chromatid damage induced by x-irradiation during the G2 phase of the cell cycle. Evidence suggested that this results from deficient DNA repair during G2 phase. Cells derived from human tumors also showed enhanced G2-phase chromosomal ...
Purpose The expression of epidermal growth factor receptor (EGFR)-CD533, a truncation mutant of the wild-type EGFR, radiosensitizes carcinoma and malignant glioma cell lines. This deletion mutant disrupts EGFR activation and downstream signaling through the formation of inhibitory dimerizations. In this study, the effects of EGFR-CD533 on other ErbB ...
Telomeres are shortened with each cell division and play an important role in maintaining chromosomal integrity and function. Telomerase, responsible for telomere synthesis, is activated in 90% of human tumor cells but seldom in normal somatic cells. Zidovudine (AZT) is a reverse transcriptase inhibitor. In this study, we have investigated the effects of {gamma}-radiation in combination with AZT ...
A study was made of the intrinsic radiosensitivity of 140 biopsy and surgical specimens of malignant head and neck tumours of different histologies. Using a soft-agar clonogenic assay, the material was assessed for the ability to grow in culture (colony-forming efficiency; CFE) and inherent tumour radiosensitivity (surviving fraction ...
Despite advances in the field of oncology, progress for patients with brain metastases and most primary brain tumors has been slow. New efforts to enhance the therapeutic index of radiation therapy are under way, including the use of radiosensitizers. Motexafin gadolinium (Xcytrin) is one such novel agent with several unique properties that enhance the cytotoxic potential of ...
5-Fluorouracil (5-FU) and 5-fluorodeoxyuridine (FdUrd, floxuridine) have activity in multiple tumors, and both agents undergo intracellular processing to active metabolites that disrupt RNA and DNA metabolism. These agents cause imbalances in deoxynucleotide triphosphate levels and the accumulation of uracil and 5-FU in the genome, events that activate the ATR- and ATM-dependent checkpoint ...
The disposition of veliparib [(R)-2-(2-methylpyrrolidin-2-yl)-1H-benzo[d]imidazole-4-carboxamide, ABT-888], a novel and potent inhibitor of poly(ADP-ribose) polymerase for the treatment of cancers, was investigated in rats and dogs after intravenous and oral administration of [(3)H]veliparib and compared with that of humans. Veliparib absorption was high. ...
Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent ...
A rapid and sensitive method was developed and validated using a liquid chromatographic method with tandem mass spectrometry detection (LC/MS/MS) for determination of veliparib (ABT-888) in plasma, bone marrow supernatant, and bone marrow cells. Sample preparation involved a single protein precipitation step by the addition of the sample with acetonitrile. ...
Methods for evaluating radiosensitivity of cervical carcinoma are described and experience in their application reported. Attempts made to predict biologic malignancy and degree of radiosensitivity from examination of pretreatment cervical biopsies showed that there is some correlation between histologic differentiation and ...
The radiosensitizing effect of two electron-affinic nitroimidazoles, metronidazole and misonidazole (Ro-07-0582), has been tested on a human malignant melanoma grown subcutaneously in the athymic mutant nude mouse. A 60Co therapy unit was used for local irradiation of the mice. Metronidazole in doses of 750 mg/kg and misonidazole in doses of 500 mg/kg were ...
Oxidative stress-mediated mitochondrial dysfunction is known to induce intrinsic pathway of apoptosis. Previously, we have shown that a combination of metabolic modifiers 2-deoxy-D: -glucose (2-DG) and 6-aminonicotinamide (6-AN) results in oxidative stress-mediated radiosensitization of malignant cells via noncoordinated expression of antioxidant defense. ...
The effect of the hypoxic cell radiosensitizer misonidazole (Ro-07-0582) has been tested on a human malignant melanoma grown subcutaneously in the athymic mutant nude mouse. A 60Co therapy unit was used for local irradiation of the animals. The tumours were exposed daily to 3.75 Gy (375 rad) over four consecutive days, to a total dose of 15.0 Gy. ...
The effect of venous infusions of vasopressin during fractionated abdominal radiation exposures was evaluated in four pairs of dogs. In each pair, the control dog was given venous infusion of saline during irradiation. The results were analyzed from clinical observation, autopsy findings, and pathological examination. It appears that venous infusion of vasopressin has a definite and reproducible ...
... TITLE: Inhibitors of Histone Deacetylases for Radiosensitization of Prostate Cancer ... Inhibitors of Histone Deacetylases for Radiosensitization ...
DTIC Science & Technology
About 0.02 to 0.05 cc of /sup 133/Xe was injected into the tumor and the clearance curve was drawn to examine the regional blood flow in the tumor. The relationship between the regional microcirculation in the tumor and the radiosensitivity was also studied. In the Ehrlich subcutaneous tumor prepared by transplanting the ascites tumor cell to the back of a mouse, the ...
