5-fluorouracil enhances protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses: A mechanism-based clinical trial

Edward V Maytin, Sanjay Anand, Margo Riha, Sara Lohser, Alejandra Tellez, Rim Ishak, Lauren Karpinski, Janine Sot, Bo Hu, Anton Denisyuk, Scott C. Davis, Angela Kyei, Allison Vidimos

Research output: Contribution to journalArticle

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Abstract

Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminole-vulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT. Results: PpIX levels were increased 2- to 3-fold in 5FU-pre-treated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant. Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk.

LanguageEnglish (US)
Pages3026-3035
Number of pages10
JournalClinical Cancer Research
Volume24
Issue number13
DOIs
StatePublished - Jul 1 2018

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Actinic Keratosis
Photochemotherapy
Fluorouracil
Clinical Trials
Coproporphyrinogen Oxidase
Ferrochelatase
Fluorometry
Photosensitizing Agents
protoporphyrin IX
Scalp
Lighting
Heme
Forearm
Squamous Cell Carcinoma
Cell Death
Biopsy
Light
Skin
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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5-fluorouracil enhances protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses : A mechanism-based clinical trial. / Maytin, Edward V; Anand, Sanjay; Riha, Margo; Lohser, Sara; Tellez, Alejandra; Ishak, Rim; Karpinski, Lauren; Sot, Janine; Hu, Bo; Denisyuk, Anton; Davis, Scott C.; Kyei, Angela; Vidimos, Allison.

In: Clinical Cancer Research, Vol. 24, No. 13, 01.07.2018, p. 3026-3035.

Research output: Contribution to journalArticle

Maytin, Edward V ; Anand, Sanjay ; Riha, Margo ; Lohser, Sara ; Tellez, Alejandra ; Ishak, Rim ; Karpinski, Lauren ; Sot, Janine ; Hu, Bo ; Denisyuk, Anton ; Davis, Scott C. ; Kyei, Angela ; Vidimos, Allison. / 5-fluorouracil enhances protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses : A mechanism-based clinical trial. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 13. pp. 3026-3035.
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abstract = "Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminole-vulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT. Results: PpIX levels were increased 2- to 3-fold in 5FU-pre-treated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75{\%} versus 45{\%} at 3 months, and 67{\%} versus 39{\%} at 6 months, respectively; these differences were statistically significant. Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk.",
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T1 - 5-fluorouracil enhances protoporphyrin IX accumulation and lesion clearance during photodynamic therapy of actinic keratoses

T2 - Clinical Cancer Research

AU - Maytin, Edward V

AU - Anand, Sanjay

AU - Riha, Margo

AU - Lohser, Sara

AU - Tellez, Alejandra

AU - Ishak, Rim

AU - Karpinski, Lauren

AU - Sot, Janine

AU - Hu, Bo

AU - Denisyuk, Anton

AU - Davis, Scott C.

AU - Kyei, Angela

AU - Vidimos, Allison

PY - 2018/7/1

Y1 - 2018/7/1

N2 - Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminole-vulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT. Results: PpIX levels were increased 2- to 3-fold in 5FU-pre-treated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant. Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk.

AB - Purpose: Actinic keratoses (AK) are precancerous lesions that can progress to squamous cell carcinoma. Photodynamic therapy (PDT) and topical 5-fluorouracil (5FU) are commonly used agents for AK. Empirical reports suggest that combining them can improve the therapeutic response. However, the optimal combined regimen was not clear in terms of proper sequence, timing, and mechanism. This clinical study explored mechanisms of action for neoadjuvantal 5FU and PDT for treatment of AK. Patients and Methods: A bilaterally controlled trial (17 patients) was performed. One side of the body (face, scalp, forearms) received 5FU pretreatment for 6 days, whereas the other side served as no-pretreatment control. Methylaminole-vulinate cream was applied to both sides for 3 hours, and protoporphyrin IX (PpIX) levels were measured by noninvasive fluorimetry and skin biopsy. After red light illumination, lesion clearance was assessed at 3, 6, 9, and 12 months after PDT. Results: PpIX levels were increased 2- to 3-fold in 5FU-pre-treated lesions versus controls. Altered expression of heme-synthetic enzymes (coproporphyrinogen oxidase and ferrochelatase) and induction of p53 were observed, probably accounting for increased PpIX and subsequent cancer cell death. Relative clearance rates after PDT with or without 5FU pretreatment were 75% versus 45% at 3 months, and 67% versus 39% at 6 months, respectively; these differences were statistically significant. Conclusions: Serial 5FU and PDT improve AK clearance by at least two mechanisms, enhanced photosensitizer accumulation and p53 induction. Because 5FU and PDT are FDA-approved modalities, the combined regimen can be readily employed in clinical practice to reduce AK burden and reduce SCC risk.

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