TXB-001, a newly-developed polymer-conjugated anthracycline: Significantly lower adverse effects in animal models of alopecia and hand-foot syndrome

Anthracycline anti-cancer drugs have been widely used in the treatment of several cancers; however, their use is limited by adverse effects (AEs). Alopecia is a common AE that is minimally invasive, but adversely affects mental health and reduces quality of life (QoL). Hand-foot syndrome (HFS) is a...

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Veröffentlicht in:Toxicology and applied pharmacology 2024-04, Vol.485, p.116912-116912, Article 116912
Hauptverfasser: Hirakata, Mikito, Tomikawa, Emi, Sakai, Chizuka, Uchida, Masashi, Okano, Tsubasa, Shimozono, Rieko, Kawai, Masakatsu, Itaba, Shoichi, Munakata, Lisa, Suzuki, Ryo, Oshida, Keiyu
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Sprache:eng
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Zusammenfassung:Anthracycline anti-cancer drugs have been widely used in the treatment of several cancers; however, their use is limited by adverse effects (AEs). Alopecia is a common AE that is minimally invasive, but adversely affects mental health and reduces quality of life (QoL). Hand-foot syndrome (HFS) is a dose-limiting AE of DOXIL, a liposomal formulation of doxorubicin (DOX). Although it is not a life-threatening condition, HFS affects function and reduces QoL. TXB-001 is a new candidate polymer-conjugated anthracycline anti-cancer drug, and modified and optimized polymerized pirarubicin (THP), known as P-THP, is expected to have low toxicity and high efficacy. The anti-cancer effects of TXB-001 were examined using the 4T1 mouse model. An alopecia mouse model and HFS rat model were used to evaluate the alopecia- and HFS-inducing effects of TXB-001 and compare their severity with existing anthracycline anti-cancer drugs. A pharmacokinetic analysis of plasma as well as chest, palmar, and plantar skin samples after the single intravenous administration of DOXIL and TXB-001 to rats was also performed. The results obtained revealed that TXB-001 exerted similar anti-cancer effects to those of DOXIL in mice, weaker alopecia-inducing effects than DOX, DOXIL, and THP in mice, and no or markedly weaker HFS-like changes than DOXIL, which induced significant histopathological changes. The results of the pharmacokinetic analysis showed the accumulation of DOXIL, but not TXB-001, in skin, particularly palmar and plantar skin samples, and these differences were considered to contribute to their HFS-inducing effects. •TXB-001 is a new candidate polymer-conjugated anthracycline anti-cancer drug.•Alopecia and hand-foot syndrome are well-known adverse effects of anthracyclines.•TXB-001 exerted weaker alopecia-inducing effects than anthracyclines in mice.•TXB-001 induced no or markedly weaker HFS-like changes than DOXIL in rat.•TXB-001 would be an anti-cancer drug for clinical use with fewer adverse effects.
ISSN:0041-008X
1096-0333
DOI:10.1016/j.taap.2024.116912