能不能預防放射治療掉髮？一種老藥的新用途 

癌症治療，有時會影響的不只癌細胞

對許多人來說，「放射治療」代表的是精準的高能輻射，瞄準並殺死深藏體內的癌細胞。但比較少人知道，這些高能輻射在穿過皮膚時，也會傷害到沿途的正常細胞。其中一個最顯而易見的副作用，就是治療範圍內的毛髮脫落，也就是所謂的「放射治療引起的禿髮」（Radiotherapy-Induced Alopecia, RIA）。

放射治療後，如果頭髮會在幾個月後重新長回來，屬於暫時性放射治療引起的禿髮。但在接受較高劑量放射線時，毛囊受損的程度可能很嚴重，導致持續性甚至永久性禿髮。對於剛經歷過癌症治療的人來說，這不只是外觀上的改變。頭髮與自我形象、心理自信密切相關，永久失去頭髮可能會讓人感到沮喪與心情低下，甚至影響日常生活中的自我認同與正常的社交。

可惜的是，儘管這個問題很普遍，目前並沒有任何經核准的藥物能有效預防放射治療引起的禿髮。醫師有時會透過調整放射線的角度或劑量，盡量減少毛囊受損，但這並非在所有情況都可行，尤其是在治療腦部或頭頸部癌症時。因此，找到一種既能保護毛囊、又不影響放射治療殺死癌細胞的辦法，一直是研究的重點。

毛囊受損的原因

要理解為什麼會掉髮，先得了解毛囊在生長期的情況。毛囊底部的「毛囊球」是頭髮生長的工廠，其中的基質細胞幾乎是全身分裂速度最快的細胞之一。這些位於毛囊球上方的短暫分裂細胞（Transit Amplifying Cells, TACs），不斷快速分裂以支持頭髮持續生長。這些細胞就像生產線上的主力工人，但也因為細胞分裂頻繁，受到放射線傷害時特別脆弱。

放射線會破壞細胞的 DNA。一旦 DNA 嚴重受損，細胞就會停止分裂，甚至啟動「自殺程式」或細胞凋亡。如果 TACs 大量死亡，毛囊便無法繼續生產頭髮，並會提前進入休止期（telogen）。在暫時性禿髮中，毛囊雖然受傷，但仍保留修復能力；經過幾個月休息，便可恢復生長。但在永久性禿髮中，損傷更深，毛囊可能被纖維組織取代，或是縮小成只能長出細軟短髮的「迷你毛囊」。這種情況往往與毛囊或其微環境受損有關。

老藥新用：前列腺素 E₂

我們的研究團隊一直在思考：如果能在放射線照射前，先保護那些最脆弱的 TACs，是否就能減少掉髮？其中一個有潛力的候選物質，就是前列腺素 E₂（PGE₂）。這是一種體內自然存在的脂質分子，長期以來被用於臨床，例如在產科誘發分娩。它也參與許多組織的修復與再生。過去有零星的動物實驗顯示，PGE₂ 可能能保護毛囊免受放射線傷害，但作用機制並不清楚。我們的假設是：如果 PGE₂ 能讓 TACs 短暫「暫停工作」，不要在放射線照射時進行 DNA 複製，就能降低它們的受損風險。如此一來，這些細胞可能存活下來，並在治療後迅速恢復工作。

小鼠實驗的結果

我們選用背部毛囊正處於生長期（anagen）的黑鼠模型。給予單次高劑量（8.5 Gy）放射線時，未經前列腺素 E₂預先施打處理的毛囊大多迅速停止生長，提早進入退化期（catagen）和休止期，造成大片掉毛，恢復期漫長。但如果在放射線照射前兩小時先注射 PGE₂，結果就不同了。雖然毛囊受到放射線傷害後最初仍出現一些細胞死亡與毛囊縮小的變化，但毛囊多能立即自行修復，並繼續恢復原來的生長期。相比提早進入休止期的毛囊，這些毛囊的停工時間大幅縮短，掉髮量也少得多。

保護作用的祕密

深入分析發現，PGE₂ 並沒有讓毛囊幹細胞加快分裂，而是讓 TACs 短暫停留在細胞週期的 G1 階段。這是一個尚未開始 DNA 複製的階段，細胞對放射線的敏感度較低。這段「暫停」持續幾個小時，剛好覆蓋了放射治療的時間窗口。結果顯示，接受 PGE₂ 的 TACs 之DNA 損傷較少，死亡率明顯下降，毛囊球內細胞數量保存得更多。毛囊因此能更快啟動修復，避免長時間停擺。此外，我們還觀察到 PGE₂ 有助於重新啟動 Wnt 訊號路徑，這對毛囊再生非常重要。

為了驗證這個機制，我們也使用了CDK4/6 抑制劑 palbociclib（已在癌症治療中使用）來讓細胞進入 G1 停滯，結果同樣能保護毛囊，效果與 PGE₂ 類似，支持了細胞週期調控可能是核心機制的結論。

臨床應用的前景

PGE₂ 作為放射治療掉髮防護劑，有幾個優勢：

1. 安全性已知：多年來已用於臨床，副作用與使用方式有清楚紀錄。
2. 作用時間短且可局部使用：只需在放射治療前短短幾小時發揮作用，可透過塗抹、凝膠或微針注射局部給藥，降低全身性影響，也減少保護癌細胞的風險。
3. 可行性高：給藥方式靈活，容易融入治療流程。

當然，在應用於患者之前，仍需進行人體毛囊的實驗室研究與臨床試驗，以確認安全性與有效性。我們也得特別注意另一個可能的風險：在某些情況下，PGE₂ 可能促進腫瘤生長，因此局部、短期、針對性使用是必要原則。

可能的第一個醫療預防選項

如果臨床試驗證實有效，PGE₂ 有望成為首個能預防放射治療掉髮的藥物。這對患者來說，不只是保留頭髮，更是保留了自我形象與心理自信。癌症治療的目標不僅是延長生命，也要讓人在治療後能回到盡可能完整的生活。避免永久性掉髮，正是提升生活品質的重要一環。

（103年度TBF學術講座、台灣大學醫學工程學系　林頌然教授）

【Prevention strategy for radiotherapy-induced alopecia】

-        A decades-old medicine may hold the key to saving patients’ hair during cancer radiotherapy.

 Could We Prevent Hair Loss from Radiotherapy? A New Use for an Old Medicine

When Cancer Treatment Affects More Than Cancer

For many people, hearing the word “radiotherapy” immediately brings to mind powerful beams targeting cancer cells deep in the body. What’s less often discussed is that these same beams can also harm healthy cells in their path. One of the most visible side effects is hair loss in the treated area. This type of hair loss, called radiotherapy-induced alopecia, can happen anywhere the radiation passes through the skin and hair follicles — often on the scalp, but sometimes on eyebrows, beards, or other body hair.

Not all radiotherapy-related hair loss is the same. Sometimes, the hair grows back in a few months, and the experience is temporary. But at higher radiation doses, the damage can be long-lasting or even permanent. For someone who has just gone through cancer treatment, this can be more than a cosmetic issue. Hair is closely tied to personal identity, self-esteem, and the way we see ourselves in the mirror. Losing it permanently after treatment can feel like an emotional aftershock, long after the cancer battle has been won.

Unfortunately, despite how common this problem is, there are no approved medicines that can protect hair from the effects of radiotherapy. Doctors can adjust radiation angles or doses to reduce hair follicle damage, but this isn’t always possible — especially when treating cancers in the brain or head and neck area. That’s why researchers have been searching for a way to shield hair follicles without interfering with the cancer-fighting effects of radiotherapy.

Understanding What Happens Inside the Hair Follicle

To appreciate why hair loss happens, it helps to understand what’s going on inside each hair follicle during growth. At the base of the follicle is the hair bulb, where specialized cells called matrix cells work nonstop to produce the hair shaft. These cells divide faster than almost any other cells in the body. Just above them are transit amplifying cells (TACs), which also divide quickly to support hair growth. These are the workhorses of hair production — and because they are so active, they are especially vulnerable to radiation.

When radiation hits, it can break the DNA inside these cells. Damaged cells often stop dividing and may die. If enough TACs are lost, the hair follicle can no longer keep growing hair, and the follicle may shrink and go into a resting phase called telogen. Over time, the body might restart the growth cycle, and the hair can regrow. But if the damage is too severe — for example, if the follicle’s stem cells or surrounding “niche” cells are injured — the follicle may never recover fully. This is what leads to persistent or permanent hair loss.

In temporary radiotherapy-induced alopecia (tRIA), the follicles are hurt but not destroyed. Hair falls out within weeks of starting radiotherapy, then slowly returns over the next few months. In persistent radiotherapy-induced alopecia (pRIA), the damage is deeper: follicles may be miniaturized (producing only fine, short hairs) or replaced by scar-like tissue. In some patients, the hair loss can even worsen over time if there’s ongoing skin inflammation from the radiation.

An Old Drug, a New Idea

Our research team has been studying ways to prevent RIA by protecting the most vulnerable cells — the TACs — during radiotherapy. One promising candidate turned out to be prostaglandin E₂ (PGE₂), a substance naturally made in the body. PGE₂ is not new to medicine; doctors have used it for decades to help induce labor in pregnant women. It also plays a role in healing and regeneration in many tissues.

Earlier experiments suggested PGE₂ might protect hair follicles from radiation, but no one had really worked out how. We wondered: could PGE₂ temporarily “pause” TACs, so they aren’t actively dividing when the radiation hits? If so, they might be less likely to suffer DNA damage, survive the treatment, and quickly restart hair production.

Testing the Theory in Mice

We used a mouse model where all the hair follicles on the back were in the active growth (anagen) phase — a perfect setup for studying hair loss. We gave the mice a single radiation dose high enough to cause significant follicle damage and hair loss. As expected, the untreated follicles responded with what’s called a dystrophic catagen reaction: they stopped growing, shrank, and entered the resting telogen phase far earlier than normal. Hair fell out, and regrowth was delayed.

But when we injected PGE₂ under the skin two hours before the radiation, the story was very different. Hair loss was greatly reduced. The follicles still showed some shrinkage at first, but instead of shutting down into catagen, many managed to repair themselves and keep growing. This is called a dystrophic anagen response — the follicle stays in growth mode while fixing the damage, which means less downtime and faster recovery.

How PGE₂ Protects Hair Follicles

We wanted to know exactly how PGE₂ was helping. Looking closely at the follicle cells, we saw that PGE₂ didn’t make the stem cells in the bulge start dividing — those stem cells were actually quite resistant to radiation damage on their own. Instead, PGE₂ was affecting the TACs in the hair bulb. These cells normally divide rapidly, but after PGE₂ treatment, many of them paused in the G1 phase of the cell cycle. This is a stage where the cell has not yet started copying its DNA. Cells in G1 are less sensitive to radiation because there’s less exposed DNA to damage.

This G1 “pause” lasted just a few hours, long enough to span the radiation treatment. During that time, fewer TACs were killed by radiation. DNA damage markers in these cells were lower, and fewer underwent apoptosis (programmed cell death). With more TACs surviving, the follicles could repair themselves quickly and keep producing hair without going into a long resting phase.

We also noticed that PGE₂ helped reactivate Wnt signaling, a molecular pathway important for hair follicle growth and regeneration. This likely added another boost to the follicles’ ability to recover.

Backing Up the Findings

To make sure the effect was really about putting TACs into G1 phase, we tried another approach: a drug called palbociclib, a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor already used in cancer treatment. This drug is known to cause G1 arrest in cells. When we gave palbociclib before radiation, it protected the hair follicles in much the same way as PGE₂, confirming that cell cycle control was the key mechanism.

Why This Matters

The idea of using PGE₂ to prevent hair loss during radiotherapy is exciting for several reasons:

1. Safety record: PGE₂ has been used in humans for decades in other medical contexts, so we already know a lot about its side effects and how to use it safely.
2. Short-acting and local: Because the protective effect only needs to last for a few hours, PGE₂ could be applied locally to the scalp before each radiotherapy session. This reduces the risk of affecting the cancer cells being targeted by the radiation.
3. Feasibility: It could be given as a cream, gel, or through tiny microneedle injections, making it practical to use in a clinic setting.

 The Road Ahead

Before PGE₂ could be offered to patients, we’d need to confirm its safety and effectiveness in human hair follicles. Laboratory studies on donated human scalp samples would be an important next step, followed by carefully designed clinical trials. We’d also need to study whether different hair types, skin thicknesses, or cancer treatment plans affect how well PGE₂ works.

We would also pay close attention to one possible concern: in some situations, PGE₂ can promote tumor growth. That’s why limiting it to local, short-term use just in the treated skin area is so important — and why human studies would include careful safety monitoring.

A Potential First in Hair Loss Prevention

If successful, this approach would represent the first medical option to protect against radiotherapy-induced alopecia. Right now, patients facing radiotherapy have to accept the possibility of permanent hair loss with no real way to prevent it. PGE₂ could change that, giving people a chance to keep more of their hair — and with it, a part of their sense of self — during and after cancer treatment.

Final Thoughts

Cancer treatment is about saving lives, but we also need to think about the life people return to afterward. Side effects like permanent hair loss may not threaten survival, but they can deeply affect emotional well-being. By finding ways to protect hair follicles during treatment, we’re not just preserving hair — we’re helping preserve dignity, identity, and confidence. Our work with PGE₂ is still in the research phase, but it points toward a future where protecting patients’ quality of life is as important as curing their disease.

(2014 TBF Chair in Biotechnology, Professor Sung-Jan Lin)