Erlotinib augmentation with dapsone for rash mitigation and increased anti-cancer effectiveness

Abstract

BackgroundThe epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has failed in many ways to be as potent in the anti-cancer role as pre-clinical studies would have suggested. This paper traces some aspects of this failure to a compensatory erlotinib-mediated increase in interleukin-8. Many other-but not all- cancer chemotherapeutic cytotoxic drugs also provoke a compensatory increase in a malignant clone’s interleukin-8 synthesis. Untreated glioblastoma and other cancer cells themselves natively synthesize interleukin-8. Interleukin-8 has tumor growth promoting, mobility and metastasis formation enhancing, effects as well as pro-angiogenesis effects.FindingsThe old sulfone antibiotic dapsone- one of the very first antibiotics in clinical use- has demonstrated several interleukin-8 system inhibiting actions. Review of these indicates dapsone has potential to augment erlotinib effectiveness. Erlotinib typically gives a rash that has recently been proven to come about via an erlotinib triggered up-regulated keratinocyte interleukin-8 synthesis. The erlotinib rash shares histological features reminiscent of typical neutrophilic dermatoses. Dapsone has an established therapeutic role in current treatment of other neutrophilic dermatoses.ConclusionThus, dapsone has potential to both improve the quality of life in erlotinib treated patients by amelioration of rash as well as to short-circuit a growth-enhancing aspect of erlotinib when used in the anti-cancer role.

Paths for Improving Bevacizumab Available in 2018: The ADZT Regimen for Better Glioblastoma Treatment

“…As predicted in 2015 and in 2016 [34,35], dapsone was shown to ameliorate anti-epidermal growth factor receptor mediated rash in 2017 [39,40], a rash mediated by VEGF containing neutrophils drawn to rash areas by IL-8 during erlotinib or cetuximab treatment but countered by dapsone. We therefore expect dapsone to augment bevacizumab by reducing neutrophil borne VEGF to glioblastomas.…”

“…In addition to antibacterial activity in treating Hansen's disease and pulmonary tuberculosis, dapsone has anti-protozoal effects and is used currently in treating Plasmodia infections. Unrelated to antibiotic activity, dapsone has found some utility in treating neutrophilic dermatoses like bullous pemphigoid, dermatitis herpetiformis, and others [33] including the neutrophilic rash caused by epidermal growth factor receptor inhibiting drugs [34,35]. In a series of six papers my colleagues and I have amply documented the rationale for using dapsone to deprive the tumors of neutrophil-delivered VEGF during the treatment of glioblastoma [36][37][38].…”

Paths for Improving Bevacizumab Available in 2018: The ADZT Regimen for Better Glioblastoma Treatment

“…Unrelated to antibiotic activity, dapsone has found some utility in treating neutrophilic dermatoses like bullous pemphigoid, dermatitis herpetiformis and others, including the neutrophilic rash caused by epidermal growth factor receptor inhibiting drugs [26]. In a series of five papers, my colleagues and I have amply documented the rationale for using dapsone to deprive the tumors of neutrophil-delivered VEGF during the treatment of glioblastoma [27,28,29,30,31].…”

The Roles of the Bone Marrow Microenvironment in Controlling Tumor Dormancy

“…206,209 This would be analogous to erlotinib dosing where titrating to rash might be most effective. 210 Capecitabine is best given with Coke™ or fresh squeezed lemon juice to assure low enough gastric pH for adequate and uniform absorption. This would be particularly important for those on proton pump inhibitors.…”