Drug discovery has always been a complex process including many phases from target validation to clinical development. Data from the Food and Drug Administration (FDA) has estimated that the elimination rate for investigational new drugs entering clinical trials is up to 80%. In recent years, many kinds of biomarkers have been used to predict response in cancer treatment and for evaluation of new drugs. By increasing the understanding of histone deactylase (HDAC) inhibitors cellular mechanism of action, we have elucidated how HDAC inhibitors exert their effect by the use of proper biomarkers. In this paper, we mainly focus on the development and potential clinical utility of HDAC inhibitor biomarkers.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, accounting for 90% of primary liver cancers, and its incidence is still increasing. While the curative treatment for HCC is surgical resection and liver transplantation, most patients are in advanced stage, and lose the chance of surgery. Other palliative treatments include radiofrequency ablation, transarterial embolization, chemotherapy, and radiotherapy. Although there are so many treatments, the prognosis of HCC is still very poor. A major obstacle for the treatment for HCC is the high frequency of tumor recurrence even after curative resection and liver transplantation. Since HCC is frequently resistant to conventional chemotherapy and radiotherapy, clinical development of novel therapeutic agents against HCC has begun in earnest. Thus far, a series of adjuvant therapies for HCC have emerged, including small molecular target agents, monocolonal antibodies, microRNA, and Chinese herbal medicine. Some agents such as sorafenib have shown an advantage in prolonging the overall survival time, and has been approved by FDA for the treatment of advanced HCC. In this article we review the current situation and prospects of adjuvant therapies for HCC.
A new series of anthranilamide derivatives were synthesized and evaluated for their antiproliferative activities against human colon carcinoma cell lines (HCT 116) and human breast adenocarcinoma cell lines (MDA-MB-231) in vitro. The bioassay results indicated that compounds 7a-7d, 11a, and 11b with flexible linkers showed promising antiproliferative activity against both cell lines. Among the compounds synthesized, 7c showed the most significant antiproliferative activity. Flow cytometric analysis indicated that 7c inhibited HCT 116 and MDA-MB-231 cell growth by inducing apoptosis in a dose-dependent manner and suppressed HCT 116 cell proliferation by G1 and S phase arrest. Compound 7c may serve as a lead candidate in the development of novel anticancer agents.
Injection of a Japanese cedar pollen suspension into silkworm hemolymph kills the silkworms. A certain species of bacteria proliferated in the hemolymph of the dead silkworms. A 16S rDNA analysis demonstrated that the proliferating bacteria were Bacillus cereus, Bacillus thuringiensis, Bacillus weihenstephanensis,and Bacillus amyloliquefaciens. Among them, B. cereus, B. thuringiensis, and B. weihenstephanensis exhibited hemolysis against sheep red blood cells and were lethal to mice. A culture filtrate of B. amyloliquefaciens showed enzyme activity toward the pectic membrane of cedar pollen. These results suggest that silkworms as an animal model are useful for evaluating the pathogenicity of bacteria attached to cedar pollen.
This open-label study assessed the pharmacokinetics of a single 400-mg oral dose of ribavirin in 6 healthy volunteers and 18 subjects with varying degrees of renal impairment (mild: creatinine clearance [CLcr] 61-90 mL/min/1.73m2, moderate: CLcr 31-60 mL/min/1.73m2, severe: CLcr 10-30 mL/min/1.73m2, n = 6 in each group). Blood and urine samples were collected pre-dose and up to 168 hours post-dose for pharmacokinetic analyses. Compared with control subjects, ribavirin area under the plasma concentration-time curve from time zero to the time of the final quantifiable sample (AUCtf) and maximum plasma concentration (Cmax) values were increased, and apparent clearance (CL/F), clearance (CLr), and amount excreted (Ae) values were reduced in subjects with renal impairment. Mean ribavirin AUCtf was increased 2- to 3-fold in patients with moderate-severe renal impairment compared with control subjects. Ribavirin CL/F and CLr were significantly correlated with CLcr. Single-dose ribavirin was safe and well tolerated in all subjects. The pharmacokinetics of ribavirin were substantially altered in subjects with stable chronic renal impairment, possibly reflecting changes in ribavirin metabolism associated with renal impairment.
Postoperative recurrence of hepato-cellular carcinoma (HCC) has a negative impact on long-term survival. According to available evidence, many systemic untargeted agents are ineffective as adjuvant therapy to prevent the recurrence of HCC following curative resection. Interferon α has potential effectiveness as adjuvant therapy for HCC in the presence of underlying conditions such as HBV or HCV infection. Oral polyprenoic acid has also proven its effectiveness according to a prospective study; however, no other studies have reported polyprenoicacid (acyclic retinoid) to be effective. Sorafenib is the only systemic molecular targeted agent that has proven effectiveness as adjuvant therapy according to a pilot study. To date, 11 randomized clinical trials are underway with different agents as adjuvant systemic drug therapy to prevent the recurrence of HCC following curative resection according to Clinicaltrial.gov. Adjuvant systemic drugs may be the most promising of all adjuvant modalities in the near future since HCC may be a systemic disease rather than a local disease.
Traditional Chinese medicine has gained increasing acceptance worldwide as a form of complementary and alternative medicine and has been used to treat systemic lupus erythematosus (SLE) inside and outside of China. Herbal medicines are generally low in cost, plentiful, and cause very little toxicity or few adverse reactions in clinical practice. However, the mechanisms by which traditional Chinese medicine treats SLE remain unclear. The immunosuppressive properties of traditional Chinese medicines and/or immunomodulation by those medicines could play an important role in their treatment of SLE.