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Background/aim: We developed a novel camptothecin analogue, CPT417, that yields reduced toxicity compared to other analogues used in chemotherapeutic regimens. In this pilot study, we assessed the activity of CPT417 against glioblastoma multiforme (GBM) cells and glioma stem cells., Materials and Methods: The human U251 GBM cell line and normal human astrocytes were cultured in parallel for clonogenic survival analysis following exposure to increasing concentrations of CPT417. Cell viability of a glioma stem cell line was assessed 5 days after exposure to a range of CPT417 concentrations., Results: CPT417 completely inhibited clonogenic survival of GBM cells at 10 nM, whereas this concentration only inhibited astrocytes by approximately 50%. Cell viability analysis of glioma stem cell cultures yielded a half-maximal response at 15 nM., Conclusion: CPT417 acts selectively against GBM cells at concentrations that are at least an order of magnitude below reported values for related alkylating agents in clinical use., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Chest radiotherapy continues to play an important role in the treatment of breast cancer, Hodgkin's lymphoma, and other malignancies. Subsequent cardiac injury has been described involving essentially all structures of the heart, with most radiation-induced injury being progressive in nature. Our understanding over the multifactorial etiology and development of radiation-associated cardiac injury has advanced, leading to improved techniques aimed at decreasing cardiac radiation exposure and associated risks. Monitoring after radiotherapy clearly appears to be indicated; however, optimal recommendations regarding cardiac screening remain difficult to establish., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Radiation therapy is essential for local tumor control for many types of cancer histologies. Technological advancements in recent years have allowed for precise irradiation of target tissues while minimizing the dose to non-target tissues. To enhance radiation damage to cancer cells and further limit the radiation effects on normal tissue, researchers have explored compounds that specifically target cancer cells and make them more sensitive to ionizing radiation. Recent radiosensitization research has focused on promising compounds that alter hypoxia, inhibit topoisomerases, interfere with microtubules, and activate caspases, among other mechanisms. Many such compounds have shown impressive results in pre-clinical trials against a variety of cell types, but their safety, efficacy and practicability in clinical trials remains to be demonstrated. This review seeks to provide an overview of recent research in radiosensitization, detailing some of the more successful compounds, and illustrating avenues for future research., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Cardiotoxicity is a well-known side-effect described in patients receiving various antineoplastic agents. With the abundance of clinical research and a heavy focus on drug development over the past decade, there has been a major shift in the use of non-specific cytotoxic drugs to molecular-targeted drug therapy. However, as a result, it has become clear that these drugs have numerous adverse effects, both on-target and off-target. Small-molecule tyrosine kinase inhibitors and other molecular-targeted agents, including monoclonal antibodies, have been the primary agents associated with cardiotoxicity. As more molecular-targeted therapies are developed, early recognition and management of drug-related cardiotoxicity will be extremely important in order to reduce morbidity and mortality. Pre-treatment evaluation with a surface electrocardiogram, echocardiography, cardiac history, and comprehensive review of concomitant medications are the current mainstay of treatment. However, much is still unknown about the potential cardiotoxic side-effects of these drug and optimal management. In the present article, we aim to review the cardiovascular implications and related cardiotoxicities associated with molecular target-based chemotherapeutic agents, with special emphasis on hypertension, cardiac dysfunction, and QT prolongation. Their implication, mechanism, and management are discussed where possible., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Hodgkin lymphoma (HL) is characterized by malignant Reed-Sternberg cells which express CD30. Current National Comprehensive Cancer Network guidelines for patients with advanced HL (stage III/IV disease) recommend adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), or escalated bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) as first-line regimens. ABVD appears to be as effective, with fewer side effects, as escalated BEACOPP. Escalated BEACOPP leads to a greater progression-free survival but no difference in overall survival. Recent advancements in technology have enabled an exciting shift to molecular-targeted cancer therapy. Brentuximab vedotin, a CD30-directed antibody conjugate, specifically targets malignant HL cells. It is approved by the Food and Drug Administration for the treatment of systemic anaplastic large-cell lymphoma and refractory HL that has progressed after autologous stem cell transplant, or after two prior multiagent chemotherapy regimens among patients ineligible to receive a transplant.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal types of cancer in the United States. Surgical resection remains the only curative treatment, but fewer than 20% of patients qualify as candidates. The past two decades saw major changes in the treatment of advanced PDA, a shift of standard protocol from 5-fluorouracil to gemcitabine and gemcitabine-based combinations, the introduction of molecular target therapy and multi-agent regimens. However, even with advancements in medicine, PDA is still extremely resistant to currently available regimens, which results in poor prognosis, with only 5.2% of patients alive at three years. This provides a challenge to scientists as they seek to find the best active regimen with the least side-effects. In this article, we review the current recommended guidelines from the National Comprehensive Cancer Network. In addition, we highlight major clinical trials since 2011.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and it is the third leading cause of cancer-related deaths worldwide. Once diagnosed with the disease, only 30-40% of patients are deemed eligible for curative intention with treatment modalities including surgical resection, liver transplantation, and chemoembolization. Eventually, most patients will receive some forms of chemotherapy in hope of prolonging life. Sorafenib is the first molecular inhibitor to be approved by the FDA for the treatment of advanced HCC. It is a tyrosine kinase inhibitor, targeting multiple molecular pathways. Prior to the arrival of sorafenib, doxorubicin was routinely used as a single drug for advanced HCC, but has shown inefficacy, with a response rate of about 15-20%. Other chemotherapy agents, such as epirubicin, cisplatin, 5-fluorouracil, etoposide and their combinations, demonstrate even lower efficacy. While being considered an advance over conventional chemotherapy, sorafenib only improves life expectancy approximately by 3 months over placebo. With that in mind, continuous efforts have been put into finding new targets and molecular pathways for possible new drug development. In this article, we summarize the current literature over the past year on chemotherapy treatment of advanced HCC.

Background: Radiation therapy for primary and secondary liver cancer has been limited due to dose-limiting radiation-associated liver injury. Stereotactic body radiation therapy (SBRT) permits higher dose to tumors while minimizing radiation to uninvolved liver. The purpose of this study was to assess the efficacy and safety of SBRT for treating primary and secondary hepatic neoplasms., Materials and Methods: We performed a systematic review of prospective clinical trials published in English., Results: Fifteen studies involving 158 patients with primary tumors and 341 patients with metastases to the liver were included. Treatment was performed in 1-10 fractions to total doses of 18-60 Gy. One year local control and overall survival rates were 50-100% and 33-100% respectively. There were 13 cases of radiation-induced liver disease and 4 grade 5, 6 grade 4, and 69 grade 3 adverse events reported., Conclusion: For patients who are unable or unwilling to undergo local therapy, SBRT is safe and efficacious for treating primary and secondary liver cancer.

Combined modality therapy using both chemotherapy and radiation has proved superior over radiation therapy alone for a variety of cancer types. While the locoregional control and survival benefits have been established, there is still much room for improvement both in terms of cancer control and normal tissue toxicity, i.e. the therapeutic ratio. Recently, the pace of research and development of both conventional cytotoxic and molecularly targeted radiosensitizers has been staggering. The aim of this paper is to bring the reader up to date on the clinical status of four promising new radiosensitizers: novel camptothecin analogs and inhibitors of poly(ADP-ribose) polymerase, histone deacetylase, and heat-shock protein 90.

A novel camptothecin derivative (TLC388) with higher efficacy and reduced toxicity has been synthesized and tested as a novel chemoradiosensitizing agent. This study investigated the mechanisms of the chemoradiosensitizing effects of TLC388 on H23 human non-small cell lung cancer (NSCLC) cells. Using the TUNEL assay, a significantly higher percentage of apoptotic cells was observed in the group treated with TLC388 plus X-ray radiation than those in groups treated with drug or radiation alone. The sensitizer enhancement ratio (SER) was 1.91. Apoptosis increased with drug concentration and radiation dose, exhibiting dose-dependent pattern. The results suggested that apoptosis could be a main mode of cell death that might underlie the increased chemoradio-sensitization of TLC388. Treatment with 30 nM of TLC388 plus 4 Gy X-ray also produced up to 42% of necrotic cells that were measured by trypan blue exclusion assay, but with TLC388 alone or 4 Gy radiation alone 9.8% or 11.1% necrotic cells were detected, respectively. An immunofluorescent staining method was employed to determine the levels of gamma-H2AX (phosphorylated H2AX, a variant of the H2A protein family, which is a component of the histone octomer in nucleosomes and is phosphorylated by kinases like ATM and ATR in the PI3K pathway, as the first step in recruiting and localizing DNA repair proteins) as a molecular biomarker of DNA double strand breaks (DSBs) in cells treated with TLC388 +/-radiation, or radiation alone. The formation of gamma-H2AX foci was observed after TLC388 or radiation exposure and when the cells were treated with 30 nM TLC388 plus radiation at a dose of 2 Gy, the percentage of cells containing gamma-H2AX foci increased significantly. Even more interesting, a markedly higher percentage (65.4%) of mitotic cells displayed gamma-H2AX foci after treatment with 30 nM TLC388 plus 0.5 Gy radiation, compared to only 5.9% or 26.1% of the M-phase cells treated with 30 nM TLC388 alone or 0.5 Gy radiation alone, respectively. It is suggested that mitotic cells become very sensitive to the production of DSBs after TLC388-radiation combined treatment and the formation of DSBs is strongly suggested to lead to the induction of apoptosis at doses lower than 4 Gy and to some necrosis at doses of 4 Gy or above. TLC388 enhances the production of DSBs and inhibits their repair, which contributes to the elucidation of the mechanisms of chemoradiosensitization of TLC388 and its development as a novel chemoradiosensitizing drug for improved radiotherapy.

When DNA damage, whether it is endogenous or exogenous, forms double stranded breaks (DSBs), it is always followed by the phosphorylation of the histone, H2AX. H2AX is a variant of the H2A protein family, which is a component of the histone octomer in nucleosomes. It is phosphorylated by kinases such as ataxia telangiectasia mutated (ATM) and ATM-Rad3-related (ATR) in the PI3K pathway. This newly phosphorylated protein, gamma-H2AX, is the first step in recruiting and localizing DNA repair proteins. DSBs can be induced by mechanisms such as ionizing radiation or cytotoxic agents and subsequently, gamma-H2AX foci quickly form. These foci represent the DSBs in a 1:1 manner and can be used as a biomarker for damage. An antibody can be raised against gamma-H2AX which can therefore be visualized by immunofluorescence through secondary antibodies. The detection and visualization of gamma-H2AX by flow cytometry allow the assessment of DNA damage, related DNA damage proteins and DNA repair. Gamma-H2AX also has other applications in the detection of genomic damage caused by cytotoxic chemical agents and environmental and physical damage, especially in the context of cancer treatment and therapy.

Background: The use of camptothecin (CPT) derivatives is limited by severe toxicity associated with the instability of their chemical structure. We have developed a stable CPT derivative (CPT417) and have investigated its biological activity in comparison to the currently used CPT analogs., Materials and Methods: The anticancer effects of CPT417 were assessed in vitro, with glioblastoma and colon cancer cell lines, and in vivo with mice bearing mammary adenocarcinoma tumors implanted subcutaneously in the flank. Cytotoxicity was assessed using vital dye exclusion, timelapse microscopy and colony formation., Results: CPT417 and topotecan inhibited glioblastoma cell growth at comparable levels and both compounds inhibited clonogenicity of colon cancer cells more effectively than irinotecan. CPT417 showed a much greater inhibition of mammary tumor growth compared to topotecan, both by intraperitoneal and oral administration., Conclusion: CPT417 shows dramatically reduced toxicity and an enhanced antitumor activity compared to topotecan.

Camptothecin (CPT) derivatives have emerged as a promising group of chemotherapeutic agents. The FDA has approved the CPT derivatives topotecan and irinotecan for second line treatment of ovarian cancer and metastatic colorectal cancer, respectively. These and other CPT derivatives have become part of the multi-million dollar industry that is dedicated to finding better chemotherapeutic agents with excellent tumor kill and less normal tissue toxicity. In order to reach this goal it is imperative to understand the details of the mechanisms of action and the targets of these drugs, as well as the cellular response to the drugs. Although investigations of CPT date back to the 1960's, most of the studies that have been added to our present knowledge were done in the last 10 years. The purpose of this paper is to review the latest insights into the CPT binding site, CPT-induced gene expression and CPT-induced pathways to apoptosis.

Taxol and taxotere are two of the most promising anticancer drugs. To determine the mechanisms responsible for cell death after exposure to low doses of taxane, PC3 cells were treated with taxol and taxotere, and observed with immunofluoroscence microscopy. Pericentriolar material dissociation and blockage of normal centrosome separation were found to result in two different abnormal spindle types; multipolar and monopolar spindles, respectively. The majority of abnormal spindles induced by taxol were monopolar spindles, whereas taxotere mostly induced abnormal multipolar spindles. Consequently, monopolar spindle mitosis resulted in cleavage failure, while multipolar spindle mitosis led to the formation of both cleavage failure and multipolar cell division. Multinucleation characterized interphase cells which had undergone cytokinesis defects. These cells subsequently became giant multinucleated cells after several rounds of cell cycle with sustained cleavage failure, and were gradually eliminated through cell death.

Efforts continue to be made in the field of oncology to find new and effective chemotherapeutic agents against cancer. From these efforts the camptothecins have emerged as a promising group of agents. Camptothecin, first discovered in 1958, was found to be an effective anti-chemotherapeutic agent, but the toxicities were too great to be used in a clinical setting. Derivatives of the original camptothecin molecule have been created by modifying one or more rings in an effort to improve the pharmacokinetics and toxicity profiles of the parent compound. This article reviews both the in vivo and in vitro characteristics of these novel agents.

The centrosome is a small organelle located near the nucleus which acts as the microtubule organizing center for the cell. Abnormalities in centrosome replication resulting in centrosome amplification have been identified in most of the common human cancers and implicated in the development of genetic instability and cancer. Research in centrosomes is evolving rapidly with identification of key regulatory proteins. This knowledge could help to explain the mechanisms of action of existing cancer treatments and also lead to the development of new molecularly-targeted therapy.

This study aimed to investigate the apoptotic effects of novel paclitaxel analogs on NCI/ADR-RES breast cancer cells. Using the colony formation assay, the cytotoxicity of three novel paclitaxel analogs were evaluated on NCI/ADR-RES cells which overexpress multidrug-resistant gene (MDR1). All three novel paclitaxel analogs exhibited significantly higher cytotoxicity on NCI/ADR-RES cells than paclitaxel. One analog, TL139, was 140 times more effective than paclitaxel. Using TUNEL and DNA fragmentation assay, remarkably increased apoptosis in the paclitaxel analog-treated cells was observed at 48-72 hours, but not in paclitaxel-treated cells. Caspases-3/7 were dramatically activated at 48-72 hours by the novel paclitaxel analogs. The enhanced activity of caspases-3/7 was evidently verified by the measurement of the cleavage of poly(ADP-ribose) polymerase (PARP). The increased activity of caspases-3/7 significantly correlated with the enhanced apoptosis and cell survival data. Treatment with paclitaxel analogs resulted in a significant amount of mitotic arrest. Using Western blot, the phosphorylation of Bcl-2 protein was found in palictaxel analog-treated cells in a time-dependent manner similar to that of mitotic arrest, thereby indicating that there existed a close correlation between Bcl-2 phosphorylation and mitotic arrest that preceded apoptosis. We conclude that novel taxane analogs could effectively kill MDR1-positive breast cancer cells via the mode of apoptosis.

Polysaccharide-K (polysaccharide-Kureha; PSK), also known as krestin, is a unique protein-bound polysaccharide, which has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. PSK and Polysaccharopeptide (PSP) are both protein-bound polysaccharides which are derived from the CM-101 and COV-1 strains of the fungus Coriolus versicolor by Japanese and Chinese researchers, respectively. Both polysaccharide preparations have documented anticancer activity in vitro, in vivo and in human clinical trials, though PSK has been researched longer and has therefore undergone more thorough laboratory, animal and clinical testing. Several randomized clinical trials have demonstrated that PSK has great potential as an adjuvant cancer therapy agent, with positive results seen in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunotherapy or biological response modifier (BRM). BRMs potentially have the ability to improve the "host versus tumor response," thereby increasing the ability of the host to defend itself from tumor progression. The mechanisms of biological response modification by PSK have yet to be clearly and completely elucidated. Some studies suggest that PSK may act to increase leukocyte activation and response through up-regulation of key cytokines. Indeed, natural killer (NK) and lymphocyte-activated killer (LAK) cell activation has been demonstrated in vivo and in vitro, and recent genetic studies reveal increased expression of key immune cytokines in response to treatment with PSK. An antimetastatic action of PSK has also been demonstrated and is perhaps attributed to its potential to inhibit metalloproteinases and other enzymes involved in metastatic activity. PSK has also been shown to cause differentiation of leukemic cells in vitro, and this effect has been attributed to induction of differentiation cytokines. PSK has further been shown to have antioxidant capacity which may allow it to play a role as a normal tissue chemo- and radio-protector when used in combination with adjuvant or definitive chemotherapy and/or radiotherapy in the treatment of cancer, while it may also enable it to defend the host from oxidative stress. Interestingly, studies have also shown that PSK may actually inhibit carcinogenesis by inhibiting the action of various carcinogens on vulnerable cell lines. This action of PSK may play a role in preventing second primary tumors when an inducing agent, such as tobacco or asbestos, is suspected and may also prevent second malignancies due to the carcinogenic effects of radiotherapy and cytotoxic chemotherapy. Another very important aspect of chemoimmunotherapy, in general is that it may be used on debilitated patients such as those with AIDS and the elderly who might otherwise be denied potentially helpful adjuvant cytotoxic chemotherapy. Further determination of the mechanisms of these anti-cancer, immunostimulating and biological response modifying effects of PSK as well as of other protein-bound polysaccharides is certainly warranted. Indeed, with modern cellular and molecular biology techniques, a better understanding of the specific molecular effects of PSK on tumor cells as well as leukocytes may be determined. Much of the research that has been done on PSK is outlined in this paper and may serve as a foundation toward determining the mechanisms of action of this and other protein-bound polysaccharides in the treatment of cancer. This information may open new doors in the development of novel strategies for the treatment of malignancies using adjuvant immunotherapy in combination with surgery, chemotherapy and/or radiotherapy.