The transdermal cream of Formestane anti-breast cancer

Introduction

4-hydroxyandrostenedione (4-OHA), named Formestane (Lentaron), is the first specific steroidal aromatase inhibitor (AI) in clinical use. It is a second-generation steroidal aromatase inhibitor and the first to be clinically used in the early 1990s. Its main drawback is that it must be administered intramuscularly in order to avoid its first-pass glucuronidation at the C-4 hydroxyl. This problem renders it unsuitable for widespread clinical use. Its intramuscular depot preparation (Lentaron®Depot) is administered at a single dose of 250 mg/patient/application once every 2 weeks.

Unfortunately, because the tedious administration method and side effects are not suited for adjuvant treatment, Lentaron was withdrawn from the market. Nevertheless, clinical trials have found that 4-OHA could still be effective when the tumour showed a relapse despite the thorough removal of E2 by nonsteroidal AIs. This clinical effect must be due to a mechanism independent of the deprivation of E2. To reuse the clinical benefits of 4-OHA on mammary carcinoma and overcome its disadvantages, Heinrich Wieland and his colleagues developed a new formulation of 4-OHA cream, which could be topically applied to the mammary gland and then penetrate through the skin and concentrate in the fatty tissue. The cream was clinically evaluated by Savetherapeutics®, a Germany-based biotech company.

Used on breast cancer

Previous studies had shown that 4-OHA given s.c. to rats markedly shrank DMBA-induced mammary carcinoma. To investigate whether 4-OHA cream had a similar effect to 4-OHA injection on breast cancer, researchers established a model of DMBA-induced mammary carcinoma in SD rats. Starting 60 days after DMBA treatment, mammary tumors were successful. DMBA-induced mammary cancer has been proven to be estrogen and progesterone receptor-positive. Similarly, the immunohistochemical results showed ER- and PR-positive in DMBA-induced tumours. Then, they used this model to repeat Brodie's results that 4-OHA at a dose of 50 mg/kg per day could diminish tumors by more than half. Likewise, the 4-OHA cream caused a significant regression of tumors.

Subsequently, to confirm the antitumor effects of the cream derived from the compound of 4-OHA, they performed UPLC to detect the concentration of active ingredients in the cream. The main peak of the cream was identical to the peak of a single compound of 4-OHA. Then, according to the calibration curve, the 4-OHA content of the cream was determined to be 2.5%–2.7%. Consequently, these findings indicated that 4-OHA cream worked in tumours as a 4-OHA injection.

Additionally, 4-OHA inhibited the proliferation of MCF-7 and ZR-75-1 cells at a dose of 1 μM. This antiproliferative action of 4-OHA correlated well with the results of the cell-cycle analysis in breast cancer cells. 4-OHA significantly arrested the cell cycle, increasing the portion of MCF-7 and ZR-75-1 cells in the G1 phase and decreasing the portion in the S phase, which further demonstrated the compound of 4-OHA.

Side effects

One of the most common side effects of Formestane is hot flashes. These sudden feelings of warmth often concentrated around the face, neck, and chest, can be uncomfortable and disruptive. Hot flashes are a frequent result of the reduced estrogen levels that Formestane induces.

Another side effect that patients may experience is joint pain or stiffness. This can manifest as a general discomfort in various joints, affecting mobility and quality of life. It's important for patients to communicate this side effect to their doctors, as there may be strategies to manage or alleviate the discomfort.

References

[1] Lanyang Gao. “The transdermal cream of Formestane anti-breast cancer by controlling PI3K-Akt pathway and the tumor immune microenvironment.” Frontiers in Immunology 14 (2023): 1041525.

[2] What are the side effects of Formestane? (patsnap.com) https://synapse.patsnap.com/article/what-are-the-side-effects-of-formestane

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