Noninvasive Optical Imaging of <scp>UV</scp>‐Induced Squamous Cell Carcinoma in Murine Skin: Studies of Early Tumor Development and Vitamin D Enhancement of Protoporphyrin <scp>IX</scp> Production

Rollakanti, Kishore R.; Anand, Sanjay; Davis, Scott C.; Pogue, Brian W.; Maytin, Edward V.

doi:10.1111/php.12503

Cited by 17 publications

(18 citation statements)

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“…More novel was our demonstration that 5FU stimulates tumor-selective increases in PpIX accumulation. Target tissue selectivity is a feature previously reported for other neoadjuvants such as methotrexate (18) and calcitriol in human psoriasis (29) and murine squamous cell carcinomas (24). Enhanced accumulation in tumor cells is important, but even more important may be the fact that 5-FU improves PpIX homogeneously within all cells in the tumor.…”

Section: Discussionmentioning

confidence: 62%

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Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Anand

Rollakanti

Brankov

et al. 2017

Molecular Cancer Therapeutics

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Photodynamic therapy (PDT), using 5-aminolevulinic acid (ALA) to drive synthesis of protoporphryin IX (PpIX) is a promising, scar-free alternative to surgery for skin cancers, including squamous cell carcinoma (SCC) and SCC precursors called actinic keratoses (AK). In the United States, PDT is only FDA approved for treatment of AK; this narrow range of indications could be broadened if PDT efficacy were improved. Toward that goal, we developed a mechanism-based combination approach using 5-fluorouracil (5-FU) as a neoadjuvant for ALA-based PDT. In mouse models of SCC (orthotopic UV-induced lesions, and subcutaneous A431 and 4T1 tumors), pretreatment with 5-FU for 3 days followed by ALA for 4 hours led to large, tumor-selective increases in PpIX levels, and enhanced cell death upon illumination. Several mechanisms were identified that might explain the relatively improved therapeutic response. Firstly, the expression of key enzymes in the heme synthesis pathway was altered, including upregulated coproporphyrinogen oxidase and downregulated ferrochelatase. Secondly, a 3- to 6-fold induction of p53 in 5-FU pretreated tumors was noted. The fact that A431 contains a mutant form p53 did not prevent the development of a neoadjuvantal 5-FU effect. Furthermore, 5-FU pretreatment of 4T1 tumors (cells that completely lack p53), still led to significant beneficial inductions, i.e., 2.5-fold for both PpIX and PDT-induced cell death. Thus, neoadjuvantal 5-FU combined with PDT represents a new therapeutic approach that appears useful even for p53-mutant and p53-null tumors.

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Section: Discussionmentioning

confidence: 62%

“…PpIX fluorescence from individual tumors was quantitated using IP Lab software (Spectra Services, Ontario, NY) and expressed as fold change over vehicle control. More details on this technique can be found in Rollakanti et al (24). …”

Section: Methodsmentioning

confidence: 99%

Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Anand

Rollakanti

Brankov

et al. 2017

Molecular Cancer Therapeutics

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“…SCC tumor‐bearing mice were pretreated with topical calcitriol, or vehicle (Aquaphor), prior to application of ALA. Using noninvasive fluorescence optical techniques, the authors confirmed that preconditioning with topical Vit D induces a preferential increase of PpIX levels in tumors (37).…”

Section: What About Vitamin D As a Possible Neoadjuvant For Pdt?mentioning

confidence: 82%

“…To mitigate that risk, it was important to ask whether topical calcitriol (instead of systemic) is effective as a neoadjuvant for skin cancer, given that systemic absorption of topical calcitriol should be low. In a study by Rollakanti et al (37), hairless mice were subjected to repeated UVB exposure in 24‐week carcinogenesis protocol to induce Squamous cell carcinoma (SCC) on their backs. SCC tumor‐bearing mice were pretreated with topical calcitriol, or vehicle (Aquaphor), prior to application of ALA.…”

Section: What About Vitamin D As a Possible Neoadjuvant For Pdt?mentioning

confidence: 99%

Vitamin D and Other Differentiation‐promoting Agents as Neoadjuvants for Photodynamic Therapy of Cancer

Maytin

Hasan

2020

Photochem & Photobiology

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The efficacy of photodynamic therapy (PDT) using aminolevulinic acid (ALA), which is preferentially taken up by cancerous cells and converted to protoporphyrin IX (PpIX), can be substantially improved by pretreating the tumor cells with vitamin D (Vit D). Vit D is one of several “differentiation‐promoting agents” that can promote the preferential accumulation of PpIX within the mitochondria of neoplastic cells, making them better targets for PDT. This article provides a historical overview of how the concept of using combination agents (“neoadjuvants”) for PDT evolved, from initial discoveries about neoadjuvant effects of methotrexate and fluorouracil to later studies to determine how vitamin D and other agents actually work to augment PDT efficacy. While this review focuses mainly on skin cancer, it includes a discussion about how these concepts may be applied more broadly toward improving PDT outcomes in other types of cancer.

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“…They found that not only the overall PPIX production was increased but also the fraction of cells that contained low PPIX levels was reduced after the treatment [50]. Until now, the following agents have been shown to improve PPIX accumulation and enhance the therapeutic response: (i) In patients, various carcinomas and psoriasis lesions pretreated with vitamin D and its derivatives [51, 52]; (ii) Skin or prostate carcinoma cells pretreated with methotrexate; (iii) Actinic keratosis lesions pretreated with retinoids [53]; (iv) Skin keratinocytes pretreated with calcium; (v) Hormone-responsive prostate cancer cells pretreated with androgens [54]. The molecular mechanism of combining differentiation therapy and ALA-PDT in cancer involves C/EBP (a transcription factor)-mediated cellular differentiation.…”

Section: Improvements In Cellular Ppix Synthesismentioning

confidence: 99%

Current Advances in 5-Aminolevulinic Acid Mediated Photodynamic Therapy

et al. 2016

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Kennedy and Pottier discovered that photodynamic therapy (PDT) could be carried out using a procedure consisting of topical application of the porphyrin-precursor, 5-aminolevulinic acid (ALA) to the skin, followed after some time by illumination with various light parameters in the 1980s. Since then, ALA-PDT has expanded enormously and now covers most aspects of dermatological disease. The purpose of this review is to discuss a range of ingenious strategies that investigators have devised for improving the overall outcome (higher efficiency and lower side effects) of ALA-PDT. The big advance of using ALA esters instead of the free acid to improve skin penetration was conceived in the 1990s. A variety of more recent innovative approaches can be divided into three broad groups: (a) those relying on improving delivery or penetration of ALA into the skin; (b) those relying on ways to increase the synthesis of protoporphyrin IX inside the skin; (c) those relying on modification of the illumination parameters. In the first group, we have improved delivery of ALA with penetration-enhancing chemicals, iontophoresis, intracutaneous injection, or fractionated laser. There is also a large group of nanotechnology-related approaches with ALA being delivered using liposomes/ethosomes, ALA dendrimers, niosomes, mesoporous silica nanoparticles, conjugated gold nanoparticles, polymer nanoparticles, fullerene nanoparticles, and carbon nanotubes. In the second group, we can find the use of cellular differentiating agents, the use of iron chelators, and the effect of increasing the temperature. In the third group, we find methods designed to reduce pain as well as improve efficiency including fractionated light, daylight PDT, and wearable light sources for ambulatory PDT. This active area of research is expected to continue to provide a range of intriguing possibilities.

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Noninvasive Optical Imaging of UV‐Induced Squamous Cell Carcinoma in Murine Skin: Studies of Early Tumor Development and Vitamin D Enhancement of Protoporphyrin IX Production

Cited by 17 publications

References 50 publications

Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Fluorouracil Enhances Photodynamic Therapy of Squamous Cell Carcinoma via a p53-Independent Mechanism that Increases Protoporphyrin IX levels and Tumor Cell Death

Vitamin D and Other Differentiation‐promoting Agents as Neoadjuvants for Photodynamic Therapy of Cancer

Current Advances in 5-Aminolevulinic Acid Mediated Photodynamic Therapy

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