Pharmacodynamic stimulation of thrombogenesis by angiotensin (1–7) in recurrent ovarian cancer patients receiving gemcitabine and platinum-based chemotherapy

Abstract

A 100 mcg/kg dose of A(1-7) was shown to produce pharmacodynamic effects on peripheral blood platelet counts, preserve planned dose intensity, and reduce Grade 3-4 thrombocytopenia following gemcitabine and platinum chemotherapy. These findings are consistent with A(1-7)-induced stimulation of thrombogenesis in the bone marrow following marrow-toxic chemotherapy.

Development of angiotensin II (1-7) analog as an oral therapeutic for the treatment of chemotherapy-induced myelosuppression

“…While these effects on stem cell populations are compelling, further study is need to assess the effect of Nle 3 -A(1-7) on neoplastic hematopoiesis and re-treatment toxicity during chemotherapy cycling, though the latter concern is assuaged by the clinical data showing that A(1-7) treatment allowed the maintenance of greater chemotherapy dose density than placebo. 9 Though A(1-7) has a well-documented ability to treat chemotherapy-induced myelosuppression, thus far, the development of Nle 3 -A(1-7) focused on its use as topical agent for healing dermal injuries. 6,[8][9][10] Therefore, in our understanding, this is the first study of Nle 3 -A(1-7) in this setting.…”

“…9 Though A(1-7) has a well-documented ability to treat chemotherapy-induced myelosuppression, thus far, the development of Nle 3 -A(1-7) focused on its use as topical agent for healing dermal injuries. 6,[8][9][10] Therefore, in our understanding, this is the first study of Nle 3 -A(1-7) in this setting. Finally, in contrast to Nle 3 -A(1-7), treatment with the ARB losartan had no progenitor effect, further supporting the functional differences between A-II blockers and Mas agonists.…”

“…8 In a Phase IIb study, A(1-7) treatment reduced the incidence and severity of thrombocytopenia in ovarian carcinoma patients receiving a combination of gemcitabine and platinum-based chemotherapy and allowed on-time and on-dose delivery of scheduled chemotherapy dose. 9 During the development of A(1-7) for hematologic disorders, an analog of A(1-7) substituted at the third position with norleucine (Nle) in place of the valine of A(1-7), Nle 3 -A(1-7) was developed for topical use. In a number of studies, Nle 3 -A(1-7) displayed a greater ability to stimulate wound healing than A(1-7).…”

Angiotensin 1 – 7 stimulation of platelet recovery

“…The increase in sensitivity of immature stem and early hematopoietic progenitor cells to the proliferative and regenerative effects of A(1 --7), alone and in combination with currently marketed hematopoietic stimulants (e.g., filgrastim), offers therapeutic opportunities. Clinical data from patients receiving chemotherapy show a significant improvement in platelet recovery following low dose (£ 100 mcg/kg/day) A(1 --7) administration in comparison to filgrastim or placebo-treated patients [47,51]. A reduction in efficacy is observed when a higher dose (300 mcg/kg/day) of A(1 --7) is administered [51].…”

“…The preservation of platelet counts was not dose dependent and there were no occurrences of thrombocytopenia in TXA127-treated patients [47]. More recently, a Phase IIb study evaluating the safety and efficacy of TXA127 in reducing the incidence and severity of thrombocytopenia in subjects receiving a combination of gemcitabine and platinum therapy for ovarian carcinoma was completed [51]. Subjects receiving up to six cycles of gemcitabine and platinum therapy were randomized in a 1:1:1 ratio to receive placebo, 100 or 300 mcg/kg/day TXA127.…”