China
Africa
Explore chapters and articles related to this topic
Alternative Tumor-Targeting Strategies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Tirapazamine (Figure 10.9) was the first hypoxia-activated prodrug to undergo clinical evaluation. The molecule contains two electrically neutral N-oxide moieties which become positively charged when reduced, a concept also used for the design of AQ4N (see below). However, it showed only modest clinical activity when used in combination with conventional chemotherapy. One explanation proposed for this disappointing result was that tirapazamine may have poor penetration into tumor blood vessels in hypoxic regions. Another potential explanation was based on the observation that, compared to their oxic counterparts, hypoxic cells are often quiescent (i.e., not replicating), and are thus less vulnerable to anti-proliferative agents such as DNA-damaging drugs and antimetabolites. Structure of tirapazamine (SR-4233).
Clinical Aspects of Head and Neck Cancer
Published in Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke, Radiotherapy and Clinical Radiobiology of Head and Neck Cancer, 2018
Loredana G. Marcu, Iuliana Toma-Dasu, Alexandru Dasu, Claes Mercke
The main purpose of predictive assays would have been to distinguish between tumours with distinct radiobiological features in order to design the treatment according to the tumours’ response. Decades of experience in head and neck radiotherapy have led to the conclusion that these cancers are usually hypoxic and more rapidly proliferating than other malignant tumours. Therefore, treatments have been adjusted according to these radiobiological properties. For instance, the change from conventionally fractionated radiotherapy to altered fractionation schedules was determined by the effect of various accelerated repopulation mechanisms on tumour behaviour during therapy. Thus, accelerated radiotherapy and even so accelerated-hyperfractionated radiotherapy, have improved both loco-regional control and overall survival in patients with unresectable head and neck tumours (Overgaard 2003; Bourhis 2006; Saunders 2010). The development of bioreductive drugs (hypoxia-activated prodrugs) as hypoxic cell sensitisers have opened new therapeutic avenues for selected groups of patients.
Personalized Dose Finding
Published in Ying Yuan, Hoang Q. Nguyen, Peter F. Thall, Bayesian Designs for Phase I–II Clinical Trials, 2017
Ying Yuan, Hoang Q. Nguyen, Peter F. Thall
The methodology was applied to design a trial of the hypoxia-activated prodrug PR104 in patients with refractory or relapsed AML or ALL (Konopleva et al., 2015) The trial was designed to study the four doses 1.1, 1.5, 1.2, 3.0 grams/m2 using the EffToxCovs method. Efficacy was defined as CR or CRp (CR without the requirement of platelet recovery) by day 42, and Toxicity was defined as regimen-related death or any grade 3 or 4 non-hematologic Toxicity within 42 days for the start of therapy. Preliminary analysis of historical data on 274 patients who satisfied the trials entry criteria included consideration of multiple models and different covariate combinations. Goodness-of-fit analyses, including computation of the Bayes Information Criterion (BIC, Schwarz, 1978) for each model, led to use of a Gaussian copula with probit link, and three covariates. Denoting the patient’s first CR duration prior to enrollment in the trial by CRD and number of prior salvage therapies by SALV, the covariates in the model were the binary indicator [CRD≥52] of the favorable history that the patient’s first CR duration was at least 52 weeks, the binary indicator [SALV=2] of the unfavorable history the patient had 2 (versus 1) previous salvage therapies, and Age. The covariate vector was Z = (Z1, Z2, Z3) = ([CRD≥52], [SALV=2], (Age-56)/100), and the linear terms were
Hypoxia-activated prodrug derivatives of anti-cancer drugs: a patent review 2006 – 2021
Published in Expert Opinion on Therapeutic Patents, 2022
Emilie Anduran, Ludwig J Dubois, Philippe Lambin, Jean-Yves Winum
Taking advantage of the oxygen concentration difference between hypoxic and normoxic areas became a significant direction for researchers in the last 30 years to develop bioreductive prodrugs, named later as hypoxia-activated prodrugs (HAP), to improve the efficacy of drugs that are ineffective against tumor cells in hypoxic microenvironments [17–20].
Emerging theranostics to combat cancer: a perspective on metal-based nanomaterials
Published in Drug Development and Industrial Pharmacy, 2022
Tejas Girish Agnihotri, Shyam Sudhakar Gomte, Aakanchha Jain
Metal-organic frameworks (MOFs) are porous coordination polymers, which have been self-assembled from ligand molecules. They have been the subject of attraction due to their high porosity, large surface area, thermostability, and ability to functionalize with different drugs or moieties. They are quite useful in the treatment of cancer because of their remarkable properties including the high binding ability to cancer cells eliciting targeted therapy, drug delivery in terms of pH stimuli, and photosensitization. There have been several methods of synthesis of MOFs such as microwave-based synthesis, solvothermal synthesis, vapor deposition synthesis, solvent-free synthesis, and electrosynthesis. The characterization methods comprise of morphological evaluation by scanning electron microscopy and atomic force microscopy, X-ray diffraction technique, and X-ray absorption spectroscopy to characterize the crystalline structure of MOFs [120]. MOFs have been widely employed in detecting biomarkers for cancer because of their distinctive features. Lanthanides are suitable candidates for functionalization with MOFs by virtue of their luminescence emission in the visible region [121]. Photodynamic therapy (PDT), one of the treatment modalities in cancer makes use of photosensitizers that are dependent on oxygen, however; on the contrary, the tumor microenvironment is in hypoxic condition making PDT ineffective. To overcome this challenge, scientists have come up with hypoxia-activated prodrugs in combination with PDT. Liu et al. [122] formulated Hf-TCPP nanoscale MOFs by solvothermal method with porphyrin being a photosensitizer agent. Tirapazamine, a prodrug was attached to Hf-TCPP MOF and further functionalized with polymer, DOPA-PIMA-PEG to make stable and controlled release delivery. Due to the higher content of porphyrin in NPs, the formulated system was able to produce a higher level of ROS, which enabled it to cytotoxic to tumor cells upon administration. MOFs have also been utilized in PTT. Indocyanine green, a photoactive dye that has been approved by US-FDA suffers from some limitations like low solubility profile, low responsiveness to theranostics, and low targeting ability to cancerous cells. To overcome these problems, Cai et al. [123] designed MOF based on hyaluronic acid–iron NPs with the incorporation of indocyanine green. The research findings showed that more than 40% of dye was loaded in MOF with high uptake into MCF-7 cells. The targeting ability of developed MOF-based NPs was also proved based on tumor xenograft models establishing a good platform for cancer imaging and therapeutic applications in cancer.