Investigation of the pH-dependent hydrolysis of a chlorin e6 hydrazide derivative as a potential photosensitizer for combined anticancer therapy

At the end of 2005 an estimated 650 000 people in China were infected with HIV among whom 75 000 were in need of ART. The Division of Treatment and Care at the National Center for AIDS/STD Control and Prevention (NCAIDS) Chinese Center for Disease Control (CCDC) has been responsible for the overall scale up of the National Free ART Program. As of December 2005 a total of 20 453 patients in 28 provinces autonomous regions and special municipalities had benefited from this national program and received free ART. The increase in access to ART however is accompanied by the risk of drug resistance development. A small body of literature already documents HIV drug resistance in China in these treated populations. These preliminary findings are consistent with the development of drug resistance observed in developed countries soon after the initiation of wide-scale HIV treatment. Therefore it is imperative that clinicians understand the causes and implications of HIV resistance in both patientcare and in the public health perspective. (excerpt)

Effect of vitamin A as a neoadjuvant agent in chemotherapy and photodynamic therapy of Rhabdomyosarcoma cells.

Development of drug resistance in cancer is one of the main challenges in chemotherapy, and many mechanisms are still unknown. In this study, we show that tumor necrosis factor alpha (TNFalpha) increases postdrug survival from 5-fluoro-2'-deoxyuridine (FdUrd) in two human colon tumor cell lines. This resulted in the development of drug-resistant cells in a TNFalpha-dependent manner. Interestingly, although the drug-resistant cells were selected using FdUrd, they are also resistant to a number of other antimetabolites in the DNA synthesis pathway in a TNFalpha-dependent manner. Only in the drug-resistant cells (p35-colo201) TNFalpha treatment resulted in G(0)-G(1) arrest but not in the parental colo201 and other cell types. Blocking TNFalpha-induced cell cycle arrest sensitized drug-resistant cells to FdUrd. TNFalpha-induced cell cycle arrest required IKK. IKK inhibition by a small molecule inhibitor or by the knockdown of IKKalpha, IKKbeta, or RelA/p65 using siRNA, but not the inhibition of JNK, MEK, p38, or caspase-8 pathways, blocked TNFalpha-induced G(0)-G(1) arrest and restored sensitivity to FdUrd of drug-resistant cells. TNFalpha reduced the transcripts and protein levels of phosphorylated retinoblastoma protein (Rb), Rb, E2F1, and Cdk4 only in drug-resistant p35-colo201 cells. This effect of TNFalpha was reversed by IKK inhibitor, suggesting that TNFalpha-induced cell cycle arrest is probably due to the reduction of Rb, E2F1, and Cdk4. Taken together, this study shows that, in vitro, TNFalpha-induced cell cycle arrest through IKK can provide a mechanism for the development of drug resistance to anti-cancer drugs, purine and pyrimidine analogues.

Combination spinal analgesic chemotherapy: a systematic review.

Combination Spinal Analgesic Chemotherapy: A Systematic Review

Simple SummaryTherapeutic options for the treatment of men with metastatic castration-resistant prostate cancer are limited. Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant efficacy in the treatment of this disease. However, responses to docetaxel are frequently curtailed by development of drug resistance, and patients eventually succumb to disease progression due to acquisition of drug resistance. In this study, we established drug-resistant prostate cancer cell lines and identified several mechanisms that may be associated with the development of drug resistance in prostate cancer. Actioning these mechanisms could provide a potential approach to re-sensitize drug-resistant cancer cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with metastatic castration-resistant prostate cancer.Docetaxel—a taxane-based chemotherapeutic agent—was the first treatment to demonstrate significant improvements in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC). However, the response to docetaxel is generally short-lived, and relapse eventually occurs due to the development of resistance. To explore the mechanisms of acquired docetaxel resistance in prostate cancer (PCa) and set these in the context of androgen deprivation therapy, we established docetaxel-resistant PCa cell lines, derived from the androgen-dependent LNCaP cell line, and from the LNCaP lineage-derived androgen-independent C4-2B sub-line. We generated two docetaxel-resistant LNCaPR and C4-2BR sub-lines, with IC50 values 77- and 50-fold higher than those of the LNCaP and C4-2B parental cells, respectively. We performed gene expression analysis of the matched sub-lines and found several alterations that may confer docetaxel resistance. In addition to increased expression of ABCB1, an ATP-binding cassette (ABC) transporter, and a well-known gene associated with development of docetaxel resistance, we identified genes associated with androgen signaling, cell survival, and overexpression of ncRNAs. In conclusion, we identified multiple mechanisms that may be associated with the development of taxane drug resistance in PCa. Actioning these mechanisms could provide a potential approach to re-sensitization of docetaxel-resistant PCa cells to docetaxel treatment and thereby further add to the life-prolonging effects of this drug in men with mCRPC.

Advanced drug delivery systems for therapeutic applications.

Pathogenic microorganisms have been a serious threat to human life and have become a public health problem of global concern. However, in the actual treatment there is a lack of efficient antimicrobial strategies which do not easily develop drug resistance; this can lead to inaccurate drug treatment that worsens the infection and even threatens life. With the emergence of a variety of drug-resistant bacteria and fungi, photodynamic therapy has gradually become one of the most promising treatment methods for drug-resistant bacteria infection; this is because it is controllable, non-invasive, and not prone to cause the development of drug resistance. Organic conjugated polymers that possess high fluorescence intensity, a large molar extinction coefficient, excellent light stability, an adjustable energy band, easy modification, good biocompatibility, and the ability to photosensitize oxygen to produce reactive oxygen species have been widely used in the fields of solar cells, highly sensitive detection systems, biological imaging, and anti-cancer and anti-microbial treatment. Photodynamic therapy is non-invasive and has high temporal and spatial resolution and is a highly effective antimicrobial treatment that does not easily induce drug resistance; it has also stimulated the scientific research enthusiasm of researchers and has become a research hotspot in the antimicrobial field. In this review, the photodynamic antibacterial applications of conjugated polymers with different structure types are summarized, and their development directions are considered.

In a recent clinical study, we showed that hypericin accumulates selectively in urothelial lesions of the bladder following intravesical administration of the compound in patients. This observation infers that hypericin, a potent photosensitizer, could be used as a selective photodynamic therapy (PDT) tool against superficial bladder cancer. In the present study we investigated the in vivo PDT activity of hypericin in transition cell carcinoma (TCC) tumors of the bladder. Both the distribution and tumor PDT response were carried out using subcutaneous heterotopic AY-27 TCC tumors in syngeneic rats. For both PDT and distribution studies, hypericin (1 or 5 mg/kg) was injected intravenously 0.5, 6 or 24 h before PDT or distribution evaluation. The data show that hypericin is a potent photosensitizer in the treatment of TCC tumors in vivo and that the interval between drug administration and photo-irradiation has a dramatic effect on the PDT outcome. Using a 0.5 h interval between drug administration and photo-irradiation the tumor regrowth study indicated that no tumor mass could me measured 9-10 days after PDT. On the contrary, lengthening the time interval between drug administration and photo-irradiation resulted in a gradual loss of PDT efficiency in these tumors. For instance, while the 6 h drug interval protocol produced a moderate PDT activity in which the tumor sizes decreased to about 50% of their original sizes 11-16 days after photo-irradiation, the 24 h interval protocol was even less effective. The distribution data indicate that the PDT efficiency of hypericin in TCC tumors corresponded to the plasma concentrations rather than to the over all concentrations in the tumor. It is therefore conceivable that the mechanism of PDT efficacy of hypericin in TCC tumors is through indirect (vascular effects) rather than through direct effects (cellular destruction) of hypericin in these tumors. In conclusion, our data indicate that hypericin is a potent photosensitizer against AY-27 TCC tumors and that the PDT efficacy of hypericin is largely determined by photosensitizer distribution in the tumor at the time of photo-irradiation.

Drug Targets and Molecular Mechanisms of Drug Resistance in Chronic Hepatitis B

The development of drug resistance in microorganisms has become one of the greatest global health challenges, as microorganisms tend to adapt to organic drugs via several mechanisms. Multi-drug resistance (MDR) in microorganisms not only increases the mortality rate of humans, but clinicians are also running out of options to treat MDR infections. A solution to this problem could be found in inorganic chemistry, where metal elements are converted in to nanoparticles that function as both drug and drug delivery agents to control microbial growth and overcome the resistance imposed on organic drugs. Nanoparticles have a high surface area to volume ratio, making them highly reactive with selective types of molecules such as bacterial/fungal cell walls. This makes nanoparticles an effective alternative to traditional chemical drugs. The development of resistance in the case of nanoparticles is almost nil. Nanoparticles of various elements have proven to be effective anti-microbial agents with several other pharmaceutical activities. Nanoparticles are also effective drug delivery agents that increase the bioavailability of drugs, enhance bioactivity, and increase drug flux into and through skin and biofilms. This chapter provides a compilation of various types of organic and inorganic nanoparticles, with their bioactivity, mode of action, synthesis, side effects, and mode of administration. Different types of nanoparticle-based drug delivery systems are summarised in this chapter, along with a summary of their organ-specific drug delivery. This report can provide a detailed understanding of nanoparticles in anti-microbial applications and aid in R&D to yield future nanomedicine.<br>

Introduction of HIV drug-resistance testing in clinical practice.

Photodynamic Therapy for Urological Malignancies: Past to Current Approaches

Optimizing Outcomes in Hepatitis C: Is Treatment Beyond 48 Weeks Ever Justified?

Drug induced superinfection in HIV and the evolution of drug resistance