Abstract

To improve current treatment options in epithelial ovarian cancer, this paper outlines how nine non-cytotoxic drugs, eight of which are marketed for non-cancer indications, can be expected to augment current cytotoxic chemotherapy. By matching what we know about the pathophysiology of epithelial ovarian cancer with the pharmacologic attributes of currently marketed non-cytotoxic drugs, nine drugs were found to match eight identified important growth facilitating paths. The nine drugs: 1) The old anti-viral drug acyclovir inhibits indolamine 2, 3- dioxygenase, an action expected to lower immunoinhibitory Treg lymphocytes; 2) Ambrisentan, marketed to lower pulmonary hypertension can be expected to lower endothelin-1 mediated growth stimulation; 3) The old anti-hypertension drug captopril inhibits matrix metalloproteinases-2 and -9. Both are used for invasion and growth signaling; 4) The old drug disulfiram used to treat alcoholism can be expected to inhibit stemness; 5 and 6) Ramelteon, a melatonin agonist marketed as a sleep aid also stimulates interleukin-2 synthesis. The antidepressant fluvoxamine increases ramelteon levels thereby amplifying interleukin-2 stimulating effects; 7) Imiquimod is a topical Toll-like receptor-7 agonist marketed to treat basal cell carcinoma and other skin cancers by host immunostimulation. It cannot be given systemically but is tolerated well intraperitoneally and can be expected to behave in a similar way in ovarian cancer, causing regression of topically exposed micrometastases after imiquimod peritoneal lavage; 8) The CXCR4 chemokine signaling receptor that plays an important role in many cancers including epithelial ovarian cancer, is blinded by plerixafor, a drug approved for bone marrow stem cell mobilization; 9) Bradykinin is active in generating ovarian cancer ascites. Also captopril risks generating supraphysiological bradykinin levels. Both aspects necessitate using icatibant, a bradykinin blocker. Such a large number of drugs opens the way to unexpected side effects but there is no immediately apparent interaction of concern with simultaneous use of these. If effective as predicted, this type of drug mix could be elevated to a principle of Comprehensive Growth Factor Inhibition as a new core treatment path in cancer.

Abbreviations: ACE, angiotensin converting enzyme; CGFI, Comprehensive Growth Factor Inhibition; EOC, epithelial ovarian cancer; interleukin-2, IL-2; TLR-7, Toll-like receptor-7.

Preamble:  "Little minds try to defend everything at once, but sensible people look at the main point only; they parry the worst blows and stand a little hurt if thereby they avoid a greater one. If you try to hold everything, you hold nothing." Frederick the Great, mid-1700's.