NSC 146109 hydrochloride

NSC 146109 hydrochloride is a selective activator of p53 with IC50 value ranges from 2.5 to >5 μg/mL [1].

Tumor protein p53 (p53) is a crucial protein in multicellular organisms and plays a pivotal role in preventing cancer formation. [1].

NSC 146109 hydrochloride is a potent p53 activator and has a higher activity than reported p53 activator RITA. When tested with breast tumor cell line MCF-7 cells, NSC 146109 hydrochloride treatment induced cell apoptosis and decreased cell viability through activating p53 expression which in turn up-regulated the expression of p21 [2]. In 16 tumor cells, NSC 146109 hydrochloride showed no clear genetic basis for the tumorigenic cell selectivity while had different affinity to different cell lines [1]. When tested with head and neck cancer (HNC) cell lines (high-expression of MDM4 while low-expression of p53, NSC 146109 hydrochloride treatment significantly suppressed cell growth and promoted cell apoptosis in a dose-dependent manner [3].

In mice model with head and neck cancer (HNC) cells subcutaneous xenograft, administration of NSC 146109 hydrochloride markedly inhibited cell growth and decreased tumor volume alone or combined with chemotherapy drug cisplatin which was regarded as a promising strategy for treating HNC in clinic [3].

References:
[1].  Dolma, S., et al., Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell, 2003. 3(3): p. 285-96.
[2].  Wang, H. and C. Yan, A small-molecule p53 activator induces apoptosis through inhibiting MDMX expression in breast cancer cells. Neoplasia, 2011. 13(7): p. 611-9.
[3].   Roh, J.L., J.Y. Park, and E.H. Kim, XI-011 enhances cisplatin-induced apoptosis by functional restoration of p53 in head and neck cancer. Apoptosis, 2014. 19(11): p. 1594-602.

Mitoxantrone hydrochloride (NSC-310739) in lymphoma. A Southwest Oncology Group study.[Pubmed:6678857]

Invest New Drugs. 1983;1(1):65-70.

The members of the Southwest Oncology Group have treated thirteen patients with Hodgkin's disease and thirty-seven with non-Hodgkin's lymphoma with mitoxantrone on the every three week schedule. While the result (3/13 responses in Hodgkin's; 9/37 responses in non-Hodgkin's lymphoma) is not striking, there is a definite antitumor activity in a very heavily pretreated group of patients. Toxicity was acceptable. Additional trials in lymphoma are planned using mitoxantrone in combination with BCNU.

Phase I-II study of pibenzimol hydrochloride (NSC 322921) in advanced pancreatic carcinoma.[Pubmed:1709152]

Invest New Drugs. 1991 Feb;9(1):53-7.

Pibenzimol is a fluorescent molecule known to bind to double stranded DNA. It also induces prolongation of the G2 phase of the cell cycle, inhibition of DNA replication and cessation of the growth of some cells in late S phase after DNA content has been doubled. It has been shown to increase the life span of mice bearing intraperitoneally implanted L1210 and P388 leukemia. These factors coupled with the affinity of pibenzimol for pancreatic tissue led us to conduct a phase I-II trial of pibenzimol hydrochloride in patients with advanced pancreatic cancer. Twenty-six patients were treated with a five day continuous infusion of pibenzimol at a dose ranging from 6-28 mg/m2/d. There were no treatment related deaths. Major toxicity was hyperglycemia which was self-limited. No objective responses were noted.

Investigational new drug-directed, 5-day repeat dose toxicity study of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) administered with or without Taxol in Sprague-Dawley rats.[Pubmed:20074267]

Basic Clin Pharmacol Toxicol. 2010 Jun;106(6):497-504.

In pre-clinical studies, 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) is a weak DNA-intercalating, hypoxia-selective cytotoxin with a promising profile as an adjuvant to radio/chemotherapy and it is about to enter phase I clinical trials. The present investigation was undertaken to further evaluate potential systemic toxicity induced by i.v. doses of NLCQ-1 alone or in combination with Taxol in Sprague-Dawley rats, in support of an investigational new drug application. Doses of NLCQ-1 were based on previous range-finding studies. In the present study, NLCQ-1 was administered either alone, at 0, 6, 9 or 12 mg/kg/dose to male rats and 8, 12 or 16 mg/kg/dose to female rats or, at 9 (male rats) and 12 (female rats) mg/kg/dose, in combination with Taxol, on a qd x 5 schedule. Taxol was administered i.v. at 3.5 mg/kg/dose 1 hr before NLCQ-1. Observations were recorded for mortality/moribundity, clinical signs of toxicity, body weights, food consumption, haematology, clinical chemistry, gross lesions at necropsy and histopathology. Blood samples were taken from 10 animals from each dose group on each of 2 days (days 8 and prior to scheduled necropsy on day 33). Administration of i.v. doses of NLCQ-1 alone, on a qdx5 schedule, resulted in no signs of toxicity over the 33-day study. Taxol-induced toxicity included minimal decreases in the group mean RBC, haemoglobin and haematocrit values, minimal increases in group mean reticulocyte counts (females), marked decreases in group mean neutrophil counts and minimal decreases in group mean monocyte and eosinophil counts. Lymphoid atrophy of thymus, atrophy of bone marrow and atrophy of the germinal epithelium of the testis were also associated with the administration of Taxol. There was no additional toxicity associated with the co-administration of NLCQ-1 and Taxol. In the present study, the 'no observable adverse effect level' for NLCQ-1, when administered on a qdx5 schedule, was >12 and >16 mg/kg/dose in male and female rats respectively. Daily administration of 9 (male rats) or 12 (female rats) mg/kg of NLCQ-1 1 hr after i.v. administration of Taxol (3.5 mg/kg) had no effect on Taxol-induced toxicity.

Investigational new drug-directed toxicology and pharmacokinetic study of 4-[3-(2-nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1, NSC 709257) in Beagle dogs.[Pubmed:20074266]

Basic Clin Pharmacol Toxicol. 2010 Jun;106(6):511-22.

4-[3-(2-Nitro-1-imidazolyl)-propylamino]-7-chloroquinoline hydrochloride (NLCQ-1), a 2-nitroimidazole-based hypoxia-selective cytotoxin has been shown to target hypoxic regions of solid tumours. The present study is one of several pre-clinical toxicology studies conducted in support of an 'investigational new drug' (IND) application to test this agent as an adjuvant to radio/chemotherapy for the treatment of cancer in humans. Twenty-four dogs were each assigned to one vehicle control group or to one of three test article-treated groups (three dogs/sex/treatment group). Intravenous (i.v.) doses of 0, 2.74, 5.48 and 10.95 mg/kg/day (54.8, 109.6 or 219 mg/m(2)/day) were administered on a per day x 5 days (qd x 5) schedule. NLCQ-1 was formulated as a solution in sterile saline at 1.5 mg/ml. None of the dogs died during this 33-day study. With few exceptions, most of the clinical signs of toxicity were noted within 2 hr following dosing in the 10.95 mg/kg/day dose group. These observations included aggressive behaviour, ataxia, tachypnea, emesis, hypoactivity, excessive salivation, tremors, and involuntary urination and defecation. Aggressive behaviour was judged to be dose-limiting. No clinical signs of toxicity were noted during the 28-day observation period that followed the 5-day dose period. Findings in a functional observation battery examination were consistent with the clinical observations. No drug-related effects were noted on the body weight or food consumption values, and no drug-related changes were noted during ocular examinations made on these animals prior to scheduled necropsy or during examination of electrocardiogram recordings made at 15 min. and 2 hr after dosing on days 1 and 5. No definitive changes in haematology, clinical chemistry or coagulation values were noted in dogs treated with NLCQ-1. NLCQ-1 was detected in the plasma of treated dogs on days 1 and 5, up to 60 min. after dosing (2.74 and 5.48 mg/kg/day) and up to 8 hr after dosing (10.95 mg/kg/day). There was a dose-related increase in maximum plasma concentration of NLCQ-1 at 5 min. after dosing; comparable concentrations were noted on days 1 and 5. No definitive test article-related lesions were noted during microscopic evaluation of tissues from dogs in this study, although lesions noted at the injection site and in the vascular tissue, lungs, thymus, prostate gland, muscle, adrenal cortex and tongue may have resulted from treatment with this drug. Any drug-related toxicity noted was readily reversible and not cumulative. No sex difference was detected in the susceptibility to NLCQ-1-induced toxicity.

Pilot screening programme for small molecule activators of p53.[Pubmed:15729694]

Int J Cancer. 2005 Jul 10;115(5):701-10.

Activation of the p53 tumour suppressor is predicted to have therapeutically beneficial effects. Many current anti-cancer therapies activate the p53 response via DNA damage. Non-genotoxic activation of the p53 pathway would open the way to long-term and possibly prophylactic treatments. We have established a simple protocol to screen small compound libraries for activators of p53-dependent transcription, and to select and characterise the most interesting hits, which include non-genotoxic activators. These compounds or their derivatives are of potential clinical interest. This approach may also lead to the identification of novel p53-activating compound families and possibly to the description of novel molecular pathways regulating p53 activity.

Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.[Pubmed:12676586]

Cancer Cell. 2003 Mar;3(3):285-96.

We used synthetic lethal high-throughput screening to interrogate 23,550 compounds for their ability to kill engineered tumorigenic cells but not their isogenic normal cell counterparts. We identified known and novel compounds with genotype-selective activity, including doxorubicin, daunorubicin, mitoxantrone, camptothecin, sangivamycin, echinomycin, bouvardin, NSC146109, and a novel compound that we named erastin. These compounds have increased activity in the presence of hTERT, the SV40 large and small T oncoproteins, the human papillomavirus type 16 (HPV) E6 and E7 oncoproteins, and oncogenic HRAS. We found that overexpressing hTERT and either E7 or LT increased expression of topoisomerase 2alpha and that overexpressing RAS(V12) and ST both increased expression of topoisomerase 1 and sensitized cells to a nonapoptotic cell death process initiated by erastin.

NSC 146109 hydrochloride is a small-molecule p53 activator that target MDMX and could be of value in treating breast cancer. NSC 146109 hydrochloride is a pseudourea derivative, promotes breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes[1].

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