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The oxygen effect and therapeutic approaches to tumour hypoxia
Published in Michael C. Joiner, Albert J. van der Kogel, Basic Clinical Radiobiology, 2018
Michael R. Horsman, J. Martin Brown, Albert J. van der Kogel, Bradly G. Wouters, Jens Overgaard
In addition, other classes of hypoxia-activated agents have been developed and tested including PR-104, TH-302 (evofosfamide), E09 (apaziquone), AQ4N (banoxantrone) and many more that have been developed and tested preclinically (46). PR-104, a 2-nitroimidazole hypoxia-activated mustard developed by Denny and Wilson in Auckland, has several features that are different from TPZ. One is that the hypoxia-produced active metabolite can diffuse from the hypoxic area to kill the surrounding oxygenated cells. This means that, unlike TPZ, PR-104 can show antitumour activity alone (36). PR-104 is a bifunctional mustard that is inactivated by nitro groups that because of their strong electron-withdrawing capacity pull reactivity away from the mustard groups that will cross-link DNA. But under hypoxic conditions cellular reductases reduce one of the nitro groups to an amine and activate the mustard moiety to become a cytotoxin, which not only kills the cells in which it is produced but also diffuses to kill both aerobic and hypoxic cells.
Update on early instillation of chemotherapy after transurethral resection of non-muscle-invasive bladder cancer
Published in Expert Review of Anticancer Therapy, 2018
Willem Oosterlinck, Karel Decaestecker
The ideal drug for EBCI should be strongly active against urothelial neoplasms. This is not the case with the current, mostly used drugs. MMC and epirubicin obtain about a 45% ablation of marker lesions. The drug is thus given in vain to about 55% of the cases plus the 5% patients who have no NMIBC. In Phase II studies, apaziquone obtained 69% complete resections and therefore it was hoped to be a more active drug for local application. The most active drug against urothelial cancer until now is cisplatinum. Shortly after its appearance on the market this drug has been tested in prevention of NMIBC. The drug provoked serious anaphylactic shocks (4 in 45 patients!) in a Belgian study that was stopped early and never published. Therefore, this dangerous experience should not be repeated. However, the search for more active molecules must go on.
Emerging intravesical drugs for the treatment of non muscle-invasive bladder cancer
Published in Expert Opinion on Emerging Drugs, 2018
Jasper Crijnen, Theo M. De Reijke
Apaziquone is a derivative of MMC and is converted into a cytotoxic agent after enzymatic activation. In the published studies, the treatment of apaziquone started 2 weeks following TURB with weekly apaziquone 4 mg/40 mL intravesically for 6 consecutive weeks [43,44]. Two phase II trials were carried out: one in intermediate-risk NMIBC resulting in a recurrence-free rate of 56% after 1 year of follow-up and 49% after 2 years of follow-up [43]. Hendricksen et al. reported a study in high-risk NMIBC and found a recurrence rate of 35% after 12 months of follow-up and 45% after 18 months of follow-up [44]. One patient (2%) had a progression to MIBC after apaziquone treatment. Side effects were comparable with those of other chemotherapeutic drugs and less than immunotherapy with BCG [43,44].