Synthesis of Taxol-Like Prostate Cancer Chemotherapeutic Agents

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.

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Chemotherapeutic agents enhance TRAIL-induced apoptosis in prostate cancer cells

Cancer Chemotherapy and Pharmacology ◽

10.1007/s00280-002-0465-z ◽

2002 ◽

Vol 50 (1) ◽

pp. 46-52 ◽

Cited By ~ 41

Author(s):

Munshi A. ◽

McDonnell T. ◽

Meyn R.

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Chemotherapeutic Agents ◽

Prostate Cancer Cells ◽

Induced Apoptosis

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Pathogenesis and Treatment of Prostate Cancer Bone Metastases: Targeting the Lethal Phenotype

Journal of Clinical Oncology ◽

10.1200/jco.2005.03.0841 ◽

2005 ◽

Vol 23 (32) ◽

pp. 8232-8241 ◽

Cited By ~ 95

Author(s):

Robert D. Loberg ◽

Christopher J. Logothetis ◽

Evan T. Keller ◽

Kenneth J. Pienta

Keyword(s):

Prostate Cancer ◽

Endothelial Cells ◽

Tumor Cell ◽

Cancer Treatment ◽

Cancer Cells ◽

Advanced Prostate Cancer ◽

Metastatic Potential ◽

Chemotherapeutic Agents ◽

Bone Microenvironment ◽

Lethal Phenotype

Traditionally, prostate cancer treatment, as well as all cancer treatment, has been designed to target the tumor cell directly via various hormonal and chemotherapeutic agents. Recently, the realization that cancer cells exist in complex microenvironments that are essential for the tumorigenic and metastatic potential of the cancer cells is starting the redefine the paradigm for cancer therapy. The propensity of prostate cancer cells to metastasize to bone is leading to the design of novel therapies targeting both the cancer cell as well as the bone microenvironment. Tumor cells in the bone interact with the extracellular matrix, stromal cells, osteoblasts, osteoclasts, and endothelial cells to promote tumor-cell survival and proliferation leading to a lethal phenotype that includes increased morbidity and mortality for patients with advanced prostate cancer. Several strategies are being developed that target these complex tumor cell–microenvironment interactions and target the signal transduction pathways of other cells important to the development of metastases, including the osteoclasts, osteoblasts, and endothelial cells of the bone microenvironment. Current and new therapies in metastatic prostate cancer will comprise a multitargeted approach aimed at both the tumor cell and the tumor microenvironment. Here, we review the current therapeutic strategies for targeting the prostate cancer–bone microenvironment and several single- and multiagent targeted approaches to the treatment of advanced prostate cancer that are under development.

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A Review of the Potential of Phytochemicals from Prunus africana (Hook f.) Kalkman Stem Bark for Chemoprevention and Chemotherapy of Prostate Cancer

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2017/3014019 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 15

Author(s):

Richard Komakech ◽

Youngmin Kang ◽

Jun-Hwan Lee ◽

Francis Omujal

Keyword(s):

Prostate Cancer ◽

Cancer Cells ◽

Treatment Options ◽

Chemotherapeutic Agents ◽

Sub Saharan Africa ◽

In Vivo Studies ◽

Prostate Cancer Cells ◽

Prunus Africana

Prostate cancer remains one of the major causes of death worldwide. In view of the limited treatment options for patients with prostate cancer, preventive and treatment approaches based on natural compounds can play an integral role in tackling this disease. Recent evidence supports the beneficial effects of plant-derived phytochemicals as chemopreventive and chemotherapeutic agents for various cancers, including prostate cancer. Prunus africana has been used for generations in African traditional medicine to treat prostate cancer. This review examined the potential roles of the phytochemicals from P. africana, an endangered, sub-Saharan Africa plant in the chemoprevention and chemotherapy of prostate cancer. In vitro and in vivo studies have provided strong pharmacological evidence for antiprostate cancer activities of P. africana-derived phytochemicals. Through synergistic interactions between different effective phytochemicals, P. africana extracts have been shown to exhibit very strong antiandrogenic and antiangiogenic activities and have the ability to kill tumor cells via apoptotic pathways, prevent the proliferation of prostate cancer cells, and alter the signaling pathways required for the maintenance of prostate cancer cells. However, further preclinical and clinical studies ought to be done to advance and eventually use these promising phytochemicals for the prevention and chemotherapy of human prostate cancer.

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Recent Developments in Treatments for Metastatic Castration-resistant Prostate Cancer—A Mechanistic Perspective

Oncology & Hematology Review (US) ◽

10.17925/ohr.2012.08.2.89 ◽

2012 ◽

Vol 08 (02) ◽

pp. 89

Author(s):

Guru Sonpavde ◽

E David Crawford ◽

◽

Keyword(s):

Prostate Cancer ◽

Abiraterone Acetate ◽

Chemotherapeutic Agents ◽

New Drugs ◽

Phase Iii ◽

Castration Resistant Prostate Cancer ◽

Microtubule Inhibitor ◽

Phase Iii Clinical Trials ◽

Castration Resistant ◽

Radium 223

Over the past decade, the treatment landscape in metastatic castration-resistant prostate cancer (CRPC) has markedly changed, with the introduction of three new chemotherapeutic agents. The mechanism of CRPC is not fully understood, but it may result from multiple pathways, including a loss or androgen receptor (AR) specificity and increased downstream signalling activity that provide multiple targets for therapeutic agents. For some years, docetaxel was the mainstay of treatment in CRPC, but recently, cabazitaxel (a microtubule inhibitor), sipuleucel-T (a cancer vaccine), and abiraterone acetate (a CYP17 inhibitor) were approved for CRPC treatment. In Phase III clinical trials, these agents have shown significant improvements in survivalover mitoxantrone (for cabazitaxel) and over placebo (for sipuleucel-T and abiraterone acetate)and were well tolerated. There are also two treatments in late-stage development, MDV3100 (an oral AR antagonist) and radium-223 (an isotope that creates breaks in double-stranded DNA). These have also shown improvements in survival in Phase III trials; their regulatory approval is expected soon. The modes of actions of the existing and new drugs in CRPC are varied, but some are complementary and investigations of different combinations of these medications are much needed; they may enhance efficacy, further extend survival, and improve outcomes in this formerly untreatable disease.

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A gene expression signature to predict high-grade prostate cancer response to oxaliplatin.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.150 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 150-150

Author(s):

Philippe Pourquier ◽

Stephane Puyo ◽

Pierre Richaud ◽

Jacques Robert ◽

Nadine Houede

Keyword(s):

Gene Expression ◽

Prostate Cancer ◽

Clinical Trials ◽

Cell Lines ◽

Gene Expression Signature ◽

Chemotherapeutic Agents ◽

Low Grade ◽

Gleason Grade ◽

High Grade ◽

Expression Signature

150 Background: Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade prostate cancers are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low. Moreover, none of these trials took into account the tumor grade. Methods: We used an in silico approach to screen for drug candidates that could be used as an alternative to taxanes, based on a 86 genes signature which could distinguish between low-grade and high-grade tumors. We extracted from the NCI60 panel databases the expression profiles of the 86 genes across 60 human tumor cell lines and the corresponding in vitro cytotoxicity data of 152 drugs and looked for correlation between their expression level and cell sensitivity to each of these drugs. Results: Among the 86 genes, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the 60 cell lines was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. This signature was validated at the functional level since repression of each of these genes conferred a significant change in the sensitivity of PCa cell lines to oxaliplatin but not cisplatin. Conclusions: Our results provide a proof of concept that gene expression signature specific from high grade PCa could be used for the identification of alternative therapies to taxanes. They could also be used to select patients for further clinical trials and as predictive markers of response to these drugs, which represents a further step forward towards personalized therapy of PCa.

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Patterns and determinants of chemotherapy-associated Clostridium difficile infection among cancer patients in the United States: A population-based study.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e19111 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e19111-e19111

Author(s):

Pramit Nadpara

Keyword(s):

Prostate Cancer ◽

Multiple Myeloma ◽

Clostridium Difficile ◽

Elderly Patients ◽

Cancer Patients ◽

Proton Pump Inhibitors ◽

Proton Pump ◽

Clostridium Difficile Infection ◽

The United States ◽

Chemotherapeutic Agents

e19111 Background: Elderly cancer patients comprise a population that is vulnerable for Clostridium difficile infection (CDI). In addition to the frequent hospitalizations, the administration of chemotherapeutic agents has been associated with the development of CDI. The objective of this study was to identify the patterns and determinants of chemotherapy-associated CDI (Chemo-CDI), in a nationwide sample of elderly patients. Methods: We used NCI’s Surveillance, Epidemiology, and End Results registry linked Medicare (SEER-Medicare) 2007-2012 files. We included patients’ aged ≥65 year, with diagnosis of lung/breast/ovarian/colorectal/prostate cancer, or lymphoma/multiple myeloma/leukemia during 2008-2011. We excluded those not receiving chemotherapy, with non-continuous Medicare enrollment, or HMO enrollment. Chemotherapy receipt was identified using appropriate ICD-9/HCPCS/CPT codes. Incidence of CDI following chemotherapy were determined by identifying any claim with primary/secondary diagnosis of CDI during the two-month follow-up period. Recurrent Chemo-CDI was identified by presence of any claim that was > 2 weeks and ≤8 weeks from the index CDI diagnosis date. Covariates including antibodies/proton pump inhibitors usage were captured and included in the analysis. Chi-square tests, and hierarchical generalized logistic models were conducted to identify determinants of Chemo-CDI. Results: We identified 41,470 elderly patients with lung/breast/ovarian/colorectal/prostate cancer, or lymphoma/multiple myeloma/leukemia diagnosis during the study years. While few (266) patients developed Chemo-CDI within one year of diagnosis, more than 50% (136) of those patients developed recurrent Chemo-CDI. Patient characteristics were not associated with risk of developing Chemo-CDI, however, significant differences were observed in antibiotics/proton pump inhibitors exposure across all cancer types (p < 0.001). Treatment for Chemo-CDI mostly comprised of Metronidazole and oral Vancomycin. Conclusions: While the incidence of Chemo-CDI is lower among patients receiving chemotherapy, the rate of recurrent Chemo-CDI was significantly higher. Strategies to prevent CDI recurrence in this population are therefore warranted. Future studies should also explore the association between increased disease burden and comorbidity, and the risk of developing Chemo-CDI.

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Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells

Prostate Cancer ◽

10.1155/2012/137163 ◽

2012 ◽

Vol 2012 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Laura Kasman ◽

Georgiana Onicescu ◽

Christina Voelkel-Johnson

Keyword(s):

Prostate Cancer ◽

Gene Therapy ◽

Histone Deacetylase ◽

Histone Deacetylase Inhibitors ◽

Chemotherapeutic Agents ◽

Viral Gene ◽

Castration Resistant Prostate Cancer ◽

Cmv Promoter ◽

Castration Resistant ◽

Adenoviral Delivery

Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.

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