Management of Postradical Prostatectomy Urinary Incontinence: A Review.

Postprostatectomy urinary incontinence has a significant impact on the quality of life of patients who undergo radical prostatectomy. Stress and overflow incontinence may result from the procedure, with sphincteric incompetence and detrusor hypocontractility implicating their development, respectively. In many cases, treatment begins with conservative approaches, including pelvic floor muscle training or biofeedback.

Inhibition of P-TEFb by DRB suppresses SIRT1/CK2α pathway and enhances radiosensitivity of human cancer cells.

Background: Positive transcription elongation factor-b (P-TEFb) is a complex containing CDK9 and a cyclin (T1, T2 or K). The effect of inhibition of P-TEFb by 5,6-dichloro-l-β-D-ribofuranosyl benzimidazole (DRB) on cell radiosensitivity and the underlying mechanisms were investigated.

Materials And Methods: Six human cancer cell lines were subjected to (3)H-uridine incorporation, cell viability and clonogenic cell survival assays; cell-cycle redistribution and apoptosis assay; western blots and nuclear 53BP1 foci analysis after exposing the cells to DRB with/without γ-radiation.

Dasatinib, a multi-kinase inhibitor increased radiation sensitivity by interfering with nuclear localization of epidermal growth factor receptor and by blocking DNA repair pathways.

Background And Purpose: Although inhibition of epidermal growth factor receptor (EGFR) signaling during radiation led to improvement of tumor control and survival, novel strategies are needed to further improve the outcome of patients with locally advanced head and neck carcinoma. Because EGFR is known to interact with c-Src kinases, the present study investigated dasatinib (BMS-354825), an inhibitor of c-Src kinases, for its efficacy in enhancing radiosensitivity of human head and neck squamous cell carcinomas (HNSCC) in vitro and examined the underlying mechanisms for this effect.

Materials And Methods: Six HNSCC lines were exposed to dasatinib, radiation, or both, and assessed for c-Src and EGFR expression, cell survival and colony forming ability.

The impact of timing of EGFR and IGF-1R inhibition for sensitizing head and neck cancer to radiation.

Background: Targeting the epidermal growth factor receptor (EGFR) improved radiotherapy outcome by 10-15% in head and neck tumors (HNSCC). We tested the therapeutic benefits of co-targeting EGFR and insulin-like growth factor-1 receptor (IGF-1R) to further enhance tumor response to radiation.

Materials And Methods: Mice bearing FaDu tumor xenografts were treated with ganitumab (previously known as AMG479, an anti-IGF-1R antibody), panitumumab (an anti-EGFR antibody), or both in combination with fractionated doses of radiation.

Mitigation and treatment of radiation-induced thoracic injury with a cyclooxygenase-2 inhibitor, celecoxib.

Purpose: To test whether a cyclooxygenase-2 inhibitor (celecoxib) could reduce mortality resulting from radiation-induced pneumonitis.

Methods And Materials: Celecoxib was given to mice twice daily for 40 consecutive days starting on the day of local thoracic irradiation (LTI) or 40 or 80 days later. C3Hf/KamLaw mice were observed for morbidity, and time to death was determined.

Poly (ADP-ribose) polymerase inhibitors in cancer treatment.

Recent research on inhibitors of poly (ADP-ribose) polymerase (PARP) has demonstrated their potential for improving cancer therapy. They inhibit protein poly (ADP-ribosyl)ation and thus affect numerous molecular and cellular functions, including DNA repair and cell survival, that are critical for such physiological and patho-physiological states as carcinogenesis, inflammation, and resistance to cancer therapy. In this review, we describe the biological basis underlying the use of these agents in cancer therapy, providing data from preclinical studies that demonstrate the synergistic interaction of PARP inhibitors with radiation and chemotherapeutics.

Noncovalent assembly of targeted carbon nanovectors enables synergistic drug and radiation cancer therapy in vivo.

Current chemotherapeutics are characterized by efficient tumor cell-killing and severe side effects mostly derived from off-target toxicity. Hence targeted delivery of these drugs to tumor cells is actively sought. In an in vitro system, we previously demonstrated that targeted drug delivery to cancer cells overexpressing epidermal growth factor receptor (EGFR+) can be achieved by poly(ethylene glycol)-functionalized carbon nanovectors simply mixed with a drug, paclitaxel, and an antibody that binds to the epidermal growth factor receptor, cetuximab.

MK-4827, a PARP-1/-2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation.

The poly-(ADP-ribose) polymerase (PARP) inhibitor, MK-4827, is a novel potent, orally bioavailable PARP-1 and PARP-2 inhibitor currently in phase I clinical trials for cancer treatment. No preclinical data currently exist on the combination of MK-4827 with radiotherapy. The current study examined combined treatment efficacy of MK-4827 and fractionated radiotherapy using a variety of human tumor xenografts of differing p53 status: Calu-6 (p53 null), A549 (p53 wild-type [wt]) and H-460 (p53 wt) lung cancers and triple negative MDA-MB-231 human breast carcinoma.

Huachansu, containing cardiac glycosides, enhances radiosensitivity of human lung cancer cells.

Aim: To assess radiosensitzing potential of huachansu (HCS) and delineate the underlying mechanisms.

Materials And Methods: Lung cancer cell lines were exposed to HCS, radiation or both and subjected to survival assays, Western blots, apoptosis assay and immunocytochemical analysis.

Results: HCS suppressed the viability of all three lung lines tested and enhanced radiosensitivity of H460 and A549 (wild-type p53) only with no effect on H1299 (p53 null) cells.

Vandetanib restores head and neck squamous cell carcinoma cells' sensitivity to cisplatin and radiation in vivo and in vitro.

Purpose: We investigated whether vandetanib, an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor (EGFR), and rearranged during transfection (RET), could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma (HNSCC).

Experimental Design: OSC-19 and HN5 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib, cisplatin, and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model. Treatment effects were assessed using clonogenic survival assay, tumor volume, bioluminescence imaging, tumor growth delay, survival, microvessel density, tumor and endothelial cell apoptosis, and EGFR and Akt phosphorylation data.

Phase I study of celecoxib with concurrent irinotecan, Cisplatin, and radiation therapy for patients with unresectable locally advanced non-small cell lung cancer.

Purpose: Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose, dose-limiting toxicities, and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan, cisplatin, and radiation therapy for patients with inoperable stage II-III non-small cell lung cancer (NSCLC).

Methods And Materials: Eighteen patients were analyzed in a phase I clinical dose-escalation trial.

Combination of anti-IGF-1R antibody A12 and ionizing radiation in upper respiratory tract cancers.

Purpose: The IGF1/IGF-1R signaling pathway has emerged as a potential determinant of radiation resistance in human cancer cell lines. Therefore we investigated the potency of monoclonal anti-IGF-1R antibody, A12, to enhance radiation response in upper respiratory tract cancers.

Methods And Materials: Cell lines were assessed for IGF-1R expression and IGF1-dependent response to A12 or radiation using viability and clonogenic cancer cell survival assays.

Are cancer stem cells radioresistant?

Based on findings that cancer cell clonogens exhibit stem cell features, it has been suggested that cancer stem-like cells are relatively radioresistant owing to different intrinsic and extrinsic factors, including quiescence, activated radiation response mechanisms (e.g., enhanced DNA repair, upregulated cell cycle control mechanisms and increased free-radical scavengers) and a surrounding microenvironment that enhances cell survival mechanisms (e.

Epithelial-to-mesenchymal transition and c-myc expression are the determinants of cetuximab-induced enhancement of squamous cell carcinoma radioresponse.

Purpose: Radiation therapy cures malignant tumors of the head and neck region more effectively when it is combined with application of the anti-EGFR monoclonal antibody cetuximab. Despite the successes achieved, we still do not know how to select patients who will respond to this combination of anti-EGFR monoclonal antibody and radiation. This study was conducted to elucidate possible mechanisms which cause the combined treatment with cetuximab and irradiation to fail in some cases of squamous cell carcinomas.

AC480, formerly BMS-599626, a pan Her inhibitor, enhances radiosensitivity and radioresponse of head and neck squamous cell carcinoma cells in vitro and in vivo.

Purpose: The present study investigated the effect of AC480, a small molecule pan-HER tyrosine kinase inhibitor, on in vitro radiosensitivity and in vivo radioresponse of a human head and neck squamous cell carcinoma cell line.

Methods: HN-5 cells were exposed to γ-radiation with and without AC480 and assayed for proliferation, clonogenic survival, apoptosis, cell cycle distribution, and DNA damage. The cells were analyzed by immunoprecipitation and western blotting for proteins involved in apoptosis, cell cycle regulation, and the EGFR pathway.

Imexon augments sensitivity of human lymphoma cells to ionizing radiation: in vitro experimental study.

Background: Imexon is an aziridine-containing small pro-oxidant molecule with promising antitumor activity in myeloma, lymphoma and lung and pancreatic cancer. Imexon is already in clinical trials in patients with advanced solid tumors. The present study examined the effects of imexon on H9 and Raji lymphoma cell lines in vitro when given in combination with ionizing radiation.

A novel Chk inhibitor, XL-844, increases human cancer cell radiosensitivity through promotion of mitotic catastrophe.

Check point kinases (Chk) play a major role in facilitating DNA repair upon radiation exposure. We tested the potency of a novel inhibitor of Chk1 and Chk2, XL-844 (provided by Exelixis Inc., CA, USA), to radiosensitize human cancer cells grown in culture and investigated the underlying mechanisms.

Enhanced response to C225 of A431 tumor xenografts growing in irradiated tumor bed.

Background And Purpose: We recently demonstrated that C225 maintenance therapy after completion of radiotherapy further increased tumor radiocurability. The present study assessed mechanisms underlying the observed improvement in C225 efficacy in pre-irradiated tissue (tumor bed).

Materials And Methods: A431 xenografts growing in pre-irradiated and non-irradiated tissue were treated with C225.

Receptor signaling as a regulatory mechanism of DNA repair.

Radiotherapy plays a crucial role in the treatment of many malignancies; however, locoregional disease progression remains a critical problem. This has stimulated laboratory research into understanding the basis for tumor cell resistance to radiation and the development of strategies for overcoming such resistance. We know that some cell signaling pathways that respond to normal growth factors are abnormally activated in human cancer and that these pathways also invoke cell survival mechanisms that lead to resistance to radiation.

Radiation Therapy Oncology Group translational research program stem cell symposium: incorporating stem cell hypotheses into clinical trials.

At a meeting of the Translation Research Program of the Radiation Therapy Oncology Group held in early 2008, attendees focused on updating the current state of knowledge in cancer stem cell research and discussing ways in which this knowledge can be translated into clinical use across all disease sites. This report summarizes the major topics discussed and the future directions that research should take. Major conclusions of the symposium were that the flow cytometry of multiple markers in fresh tissue would remain the standard technique of evaluating cancer-initiating cells and that surrogates need to be developed for both experimental and clinical use.

Single nucleotide polymorphism at rs1982073:T869C of the TGFbeta 1 gene is associated with the risk of radiation pneumonitis in patients with non-small-cell lung cancer treated with definitive radiotherapy.

Purpose: In search of reliable biologic markers to predict the risk of normal tissue damage by radio(chemo)therapy before treatment, we investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor 1 (TGFbeta1) gene and risk of radiation pneumonitis (RP) in patients with non-small-cell lung cancer (NSCLC).

Patients And Methods: Using 164 available genomic DNA samples from patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped three SNPs of the TGFbeta1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by polymerase chain reaction restriction fragment length polymorphism method. We used Kaplan-Meier cumulative probability to assess the risk of grade > or = 3 RP and Cox proportional hazards analyses to evaluate the effect of TGFbeta1 genotypes on such risk.

The role of apoptosis in radiation oncology.

Purpose: Apoptosis, as a mode of cell death in irradiated cell populations, has been the subject of literarily hundreds if not thousands of published reports over the past few years. However, in spite of the large body of knowledge related to this subject, the role of apoptosis in determining tumor response to radiotherapy has been and remains poorly understood and controversial. Indeed, some previous reviews have suggested that apoptosis may not be important in this context.

Cancer stem cells and tumor response to therapy: current problems and future prospects.

The presence of a subpopulation of cells within tumors, so-called cancer stemlike cells, that is uniquely capable of reestablishing the tumor during and after definitive radio(chemo)therapy and must be effectively controlled for a long-term cure is being increasingly appreciated. The existence and physiology of a rare cancer cell population, termed cancer cell clonogens, with similar properties has been extensively described in the radiobiology literature for several decades based on studies using tumor cells transplanted into syngeneic or immunodeficient animals. The earlier studies have identified important features that govern tumor establishment; tumor growth and homeostasis; and therapeutic resistance, including clonogen number, tumor type, vascular status, hypoxia, repopulation dynamics during treatment, and immunologic and microenvironmental status.

Combining molecular therapeutics with radiotherapy for head and neck cancer.

In the last decade, research focus has shifted to testing rapidly emerging classes of agents that specifically target signaling pathways within tumor cells or microenvironment. Though their effects given as single agents are generally limited, many of these compounds have the capability to sensitize tumors to radiation or cytotoxic drugs. Actively investigated approaches include combining anti-EGFR agents, bioreductive hypoxic cell toxins, anti-angiogenesis agents, or inhibitors of multiple signaling pathways with radiotherapy.

Celecoxib induced tumor cell radiosensitization by inhibiting radiation induced nuclear EGFR transport and DNA-repair: a COX-2 independent mechanism.

Purpose: The purpose of the study was to elucidate the molecular mechanisms mediating radiosensitization of human tumor cells by the selective cyclooxygenase (COX)-2 inhibitor celecoxib.

Methods And Materials: Experiments were performed using bronchial carcinoma cells A549, transformed fibroblasts HH4dd, the FaDu head-and-neck tumor cells, the colon carcinoma cells HCT116, and normal fibroblasts HSF7. Effects of celecoxib treatment were assessed by clonogenic cell survival, Western analysis, and quantification of residual DNA damage by gammaH(2)AX foci assay.