Advances in the Treatment of Brain Metastases
Kishan J. Pandya, Julie R. Brahmer, Manuel Hidalgo in Lung Cancer, 2016
Other chemotherapeutic agents have been explored and preliminary data are equivocal. Topotecan, a selective topoisomerase inhibitor, is an established treatment in small-cell lung cancer that has been shown to have single-agent and combined activity with WBRT (103,104). Gliadel wafer, biodegradable polymer containing 3.85% carmustine [1,3-bis(2-chloroethyl)-1-nitrosourea], which is a type of interstitial chemotherapy placed in the surgical bed following surgery, combined with surgery and WBRT has been evaluated in patients with brain metastases with encouraging results (105). However, in a phase II randomized study of 42 patients randomized to receive WBRT alone (20 Gy in 5 fractions) or WBRT plus concomitant carboplatin, median survival (4.4 months vs. 3.7 months, P = 0.64) and objective response (10% vs. 29%, P = 0.24) remained extremely poor and a significant improvement was not found in either arm (106).
Recent Advances in Repositioning Non-Antibiotics against Tuberculosis and other Neglected Tropical Diseases
Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay in Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Tricyclic antidepressants and selective serotonin reuptake inhibitors: Antidepressant drugs are the mainstay for major depressive disorder and elicit their effects through blocking the reuptake of serotonin as well as norepinephrine. The majority of these antidepressants bear structural resemblance to phenothiazines (Krystal 2011). Godbole et al. docked libraries of FDA approved drugs into the homology model for Mtb topoisomerase I, an enzyme responsible for maintaining genome topology during DNA replication and transcription. From this in silico screening, compounds with a favourable docking score including imipramine 45 and norclomipramine 46 were selected for further evaluation against Mtb (Figure 3). Both drugs displayed some antimycobacterial activity against Mtb (MIC 250 μM and 60 μM, respectively) and also inhibitory effects against the topoisomerase enzyme. Moreover, imipramine acted synergistically with moxifloxacin, a well-known type II topoisomerase inhibitor (Godbole et al. 2015). The antitubercular effects of selective reuptake inhibitors, fluoxetine 47 (MIC 69.4 μM) and sertraline 48 (MIC 59.0 μM), have also been demonstrated (Figure 3). Both antidepressants displayed a dose-dependent growth restriction of Mtb after 72 hr treatment in resting primary murine macrophages. The study also showed that accumulation of protonatable forms of the drugs in macrophages is partially pH-dependent (Schump et al. 2017).
Therapy with Oncolytic Clostridium novyi-NT: From Mice to Men
Ananda M. Chakrabarty, Arsénio M. Fialho in Microbial Infections and Cancer Therapy, 2019
Due to their poor specificity, nontargeted chemotherapeutic agents inevitably have substantial toxicity. One way to reduce their toxicity is to encapsulate the cytotoxic drugs in liposomes. Liposomes are phospholipid-based spherical vesicles ~100 nm in diameter and can preferentially accumulate in tumor tissue through the EPR effect as discussed earlier. Once inside the tumor tissue, they slowly release their payload, raising local drug concentrations. C. novyi-NT can augment the efficacy of liposomal drugs through two distinct mechanisms. First, the local inflammation in response to C. novyi-NT infection has been shown to increase vascular permeability, further enhancing the accumulation of liposomes in the infected tumor and resulting in a remarkable increase in the tumor-to-blood ratio of systemically administered liposomes [118]. Second, the hemolysins and a lipase (NT01CX2047) named liposomase are able to disrupt the lipid bilayer of the liposomes, leading to accelerated release of the drug content [100]. Through these mechanisms, C. novyi-NT was able to increase drug exposure of the tumor cells approximately sixfold without increasing drug concentrations in normal tissues. Consequently, approximately 65% of mice carrying CT26 or HCT116 tumors were cured by the combination treatment with C. novyi-NT spores and Doxil, compared to 0% by Doxil alone. Notably, combination with heat-inactivated C. novyi-NT spores did not show enhanced tumor regression. Similar therapeutic results were also obtained with liposomal CPT-11 (irinotecan), which is a topoisomerase inhibitor widely used in cancer therapy. Thus, this approach is in principle applicable to a variety of chemotherapeutic agents that can be encapsulated in a liposome.
A novel series of pyrazole-platinum(II) complexes as potential anti-cancer agents that induce cell cycle arrest and apoptosis in breast cancer cells
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Robert Czarnomysy, Arkadiusz Surażyński, Anna Muszynska, Agnieszka Gornowicz, Anna Bielawska, Krzysztof Bielawski
The goal of our work was to synthesise six novel pyrazole complexes of platinum(II) (Figure 1) and demonstrate that the synthesised compounds triggered a pro-apoptotic cascade in breast cancer cells. The advantage of pyrazole compounds is the ease of complexation of such metals as copper, ruthenium, palladium, or platinum, which strengthens their therapeutic effect. It can be concluded that the effect of ligands and corresponding metal-complexes depends not only on the specific features in the auxiliary ligand and metal ion, but also on cancer cell type. Moreover, results from the last studies suggest that both ancillary ligand and intercalative ligand influence the degree of binding of these complexes to DNA as a result of which the majority of the metal-pyrazole complexes possessed anti-proliferative activities against cancer cell lines15–17. Additionally, various pyrazole and pyrazoline derivatives have been identified as inhibitors of cyclin-dependent kinase18 and vascular endothelium growth factors19. Pyrazoloacridine was identified as a DNA topoisomerase inhibitor. It inhibited malignancy and induced apoptosis in myeloma and leukemia cells and displayed pre-clinical activity in myeloma and leukemia cells both in vitro and in vivo20. In view of the above, we developed a series of novel pyrazole-platinum(II) complexes that exhibited promising anti-tumor activity.
Small molecule DNA-PK inhibitors as potential cancer therapy: a patent review (2010–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Suwen Hu, Zi Hui, Frédéric Lirussi, Carmen Garrido, Xiang-Yang Ye, Tian Xie
DNA damages appear to be the primary cause of cancer [11], and deficiencies in DNA repair genes likely underlie many forms of cancer. As the key node within the DDR [12–17], DNA-PK could be the potential target for cancer therapy [18–21]. In fact, research studies have shown that dysregulation of DNA-PK is not only linked to different types of cancer [12–14,18–31] but also to HIV infections [32–34] and age-related diseases (such as obesity, premature aging, Alzheimer’s disease, etc.) (Figure 2) [35–38]. In clinical trials, DNA-PK inhibitors are being investigated both as monotherapy agents and in a combination strategy. Limited available data indicate that monotherapy of nedisertib (M3814) might have limitation of minimal efficacy. However, the result does not rule out the monotherapy potential for DNA-PK inhibitors. Goldberg et al. recently observed some extent of anti-tumor efficacy with their highly selective DNA-PK inhibitor AZD7648 in an ataxiatelangiectasia mutated kinase (ATM) KO FaDu model [39]. In the combination strategy, a DNA-PK inhibitor is typically paired with a DSB inducer such as radiation, an inhibitor of topoisomerase II such as doxorubicin, or inhibitors of other key components of the DDR such as of poly ADP-ribose polymerase (PARP) olaparib. Yanai et al. [40] reported that the DNA-PK inhibition by NU7441 enhances the chemosensitivity to topoisomerase inhibitor in non-small cell lung carcinoma cells.
Investigational antibody-drug conjugates in clinical trials for the treatment of breast cancer
Published in Expert Opinion on Investigational Drugs, 2021
Alicia F. C. Okines, Lara Ulrich
A second anti-HER2 ADC, Trastuzumab deruxtecan (T-DXd), has recently been approved following the unprecedented results of the phase 2 DESTINY-Breast-01 trial which reported an overall response rate (ORR) of 61.4% in patients exposed to a median of six prior lines of therapy for HER2+ MBC [9]. Its efficacy stems from its high drug-to-antibody ratio (DAR) (approximately 8 compared to 3–4 with T-DM1), the cleavable tetrapeptide-based linker and high membrane permeability of the potent topoisomerase inhibitor payload, allowing it to exert a bystander effect on surrounding HER2-low or even HER2-negative tumor cells [10]. This preclinical observation also translated into benefit in the HER2-low expansion cohort (HER2 1+ or 2+/FISH negative) [11], with an ORR of 37% after a median of 7.5 lines of treatment and a median duration of response of 10.4 months [11]. The phase 3 DESTINY-Breast-04 will further clarify the benefit of T-DXd vs TPC in HER2-low MBC patients and DESTINY BREAST-02 (versus TPC) and −03 (vs T-DM1) will soon provide randomized phase 3 data in HER2+ MBC.
Related Knowledge Centers
- Anthracycline
- Camptothecin
- Coumarin
- DNA Gyrase
- DNA Repair
- Nalidixic Acid
- Topoisomerase
- Apoptosis
- Catenane
- Epipodophyllotoxin