Equivalent chemotherapy efficacy against leukemia in mice treated with topical vasoconstrictors to prevent cancer therapy side effects

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Abstract

Topically applied vasoconstrictor is a new strategy to prevent oral mucositis and alopecia, two complications of chemotherapy and stem-cell transplant. We sought to determine whether mice treated with topical vasoconstrictor minutes before chemotherapy to suppress L1210 leukemia would develop a vasoconstrictor-induced L1210 cell sanctuary, and with it, significantly worse survival outcomes. B6D2F1 mice received 104 mouse L1210 leukemia cells via retro-orbital intravenous injection and were then divided into treatment groups, which included: (i) no further treatment, (ii) a single, sub-curative, intraperitoneal dose of cyclophosphamide (90 μg/gm bw) 24 hr after L1210 cell inoculation, (iii) topical epinephrine (25–400 mM) to clipped dorsal backs 20 min before cyclophosphamide or (iv) orotopical phenylephrine (16–130 mM), epinephrine (10 mM) or norepinephrine (25 mM) 20 min before cyclophosphamide. All mice were then followed until day of death. Differences in median survival time and percent survival between mice receiving cyclophosphamide alone and mice treated with either orotopical phenylephrine, epinephrine or norepinephrine; or topical epinephrine before cyclophosphamide were not significantly different. A discernible leukemia sanctuary was not created by topical vasoconstrictor treatment prior to chemotherapy; there was no significant difference in leukemia progression between untreated mice and those treated with either orotopical or topical vasoconstrictor before chemotherapy. We have opened a Phase I/IIa dose escalation trial to evaluate the safety and efficacy of orotopical phenylephrine in preventing oral mucositis in subjects undergoing hematopoietic stem cell transplant conditioning with cyclophosphamide plus total body irradiation. This could provide a cost-effective and convenient method to prevent oral mucositis.

What's new?

Thanks to a new strategy of topical vasoconstrictor application, it may be possible to suppress oral mucositis and alopecia, potentially severe side effects of chemotherapy. However, whether topical vasoconstriction, which limits skin and mucosal exposure to cancer therapy, also provides a sanctuary for potentially relapsing tumor cells is unknown. Here, no detectable sanctuary of L1210 leukemia cells was formed in mice treated with orotopical or topical vasoconstrictor before systemic cyclophosphamide was administered, even at topical vasoconstrictor doses well above those imagined for clinical use. The strategy is being investigated further in a newly opened Phase I/IIa trial.

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