November 28, 2014

Safely specific (a.k.a a diseased tissue-specific way of generating a systemic response)

An August 2014 Drug Discovery Today article entitled Loco-regional cancer drug therapy: present approaches and rapidly reversible hydrophobization (RRH) summarized the shortcoming of systemic chemotherapy:
"Insufficient drug uptake by solid tumors remains the major problem for systemic chemotherapy. Many studies have demonstrated anticancer drug effects to be dose-dependent, although dose-escalation studies have resulted in limited survival benefit with increased systemic toxicities."
A similar criticism -- that is, the cost-benefit of systemic toxicity and greater survival -- could be made of checkpoint inhibitors (e.g., anti-CTLA-4s, anti-PD-1s, anti-PD-L1s), although there presumably is greater drug intake of these immunotherapies than chemotherapies.

Craig has long said (paraphrasing) one of the keys to solving the problem of cancer -- to generating correct, sustainable and thus successful systemic responses -- was to solve the problem of specificity. Other contributors to this proper response included route of delivery, and how the therapeutic or therapy in question induced cells to die. Specificity, manner of cell death, and route of delivery all importantly contribute to the safety, robustness and durability of a therapeutic or therapy's correct and successful systemic response.

The Drug Discovery Today article above continues:
"One solution to this has been the idea of loco-regional drug treatments, which offer dramatically higher drug concentrations in tumor tissues while minimizing systemic toxicity." {Underlined emphasis is mine}
Once they knew rose bengal (PV-10) had the necessary kind of specificity (and thus solved this problem) -- destroying only diseased tissue while leaving healthy tissue untouched or unaffected -- Craig contends they knew the main problem mostly was solved.

Other agents induce autophagy (where cells eat themselves). Can those agents induce this action only in cancerous cells, and not normal ones too?

Other agents can be delivered intralesionally or intratumorally, with the goal of delivering more drug product into the tumor. Without specificity, however, would not both the tumor and its surrounding normal tissue be affected, leaving a confused immune system to try and sort out what it must and must not do?

Craig believed a loco-regional agent could generate the correct systemic response, but needed a diseased tissue-specific way of doing so to make it practically effective and sufficiently safe: PV-10 (rose bengal).

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