PHOTOCHEMOTHERAPY

Introduction

Phototherapy and photochemotherapy are treatment methods in which ultraviolet or visible radiation is used to induce a therapeutic response either alone or in the presence of a photosensitizing drug respectively.

Phototherapy using UVB or high-dose UVA-I is efficacious in selected dermatological diseases.

To be effective, the incident radiation must be absorbed by a target or chromophore in the skin.

 In phototherapy the chromophore is
endogenous while in photochemotherapy it must be administered exogenously.

Electromagnetic radiation

Electromagnetic radiation is defined by its wavelength and frequency.

It  is  classified into different regions based on its photon energy.

For therapeutic purposes, dermatologists are most concerned with :

(UV) B (290–320 nm), A-I (320–340 nm), and A-II (340–400 nm) and visible (400–800 nm) spectrum.

Electromagnetic radiation

 UVB is the most erythrogenic and melanogenic.

It is the major action spectrum for sunburn, tanning, skin cancer, and photoaging.

The longer wavelengths of UVA are a thousand times less erythrogenic than UVB. 

However, they penetrate more deeply into the skin and contribute substantially to photoaging and photosensitivity diseases.

They also enhance UVB-induced erythema and increase the risk of skin carcinogenesis.

Visible radiation may augment the severity of some photosensitive eruptions.

Cautions in photochemotherapy

Patients treated with these modalities should be monitored for concomitant use of other potential photosensitizing medications before initiation of therapy.

Such drugs include phenothiazines, thiazides, sulphonamides, NSAIDs, sulfonylureas, tetracyclines, and benzodiazepines.

   

   

     Photochemotherapy

i.          PUVA (Psoralens and UVA)

Photochemotherapy is exposure of the patient to light of an appropriate wavelength after topical application or oral ingestion of a photosensitizing drug.

The most common photosensitizing drugs used in dermatology are synthetic psolarens.

PUVA (Psoralens and UVA)

Psoralens belong to the furocoumarin class of compounds.

They occur naturally in many plants, including limes, lemons, figs, and parsnips.

Two psoralens, 8-methoxypsoralen (methoxsalen) and 4, 5, 8-trimethylpsoralen are used therapeutically.

Methoxsalen is preferred primarily because of its superior GI absorption.

Orally administered 8-methoxypsoralen followed by UVA (PUVA) is employed in the treatment of vitiligo, psoriasis, and cutaneous T-cell lymphoma.

Pharmacokinetics

The psoralens are absorbed rapidly after oral administration.

Photosensitivity typically is maximal 1–2 hours after ingestion of methoxsalen.

There is significant but saturable first-pass elimination in the liver, which may account for variations in plasma levels among individuals after a standard dose.

Methoxsalen has a serum t1/2 of approximately 1 hour, but the skin remains sensitive to light for 8–12 hours.

Despite widespread drug distribution throughout the body, it is photoactivated only in the skin where the UVA penetrates.

Mechanisms of action

The action spectrum for oral PUVA is between 320 and 400 nm.

Psolarens form covalent linkages with pyrimidine bases in DNA when exposed to light of an appropriate wavelength. 

In addition, if oxygen is present, reactive oxygen species are also generated.

Mechanisms of action

Additional mechanisms that contribute to use of PUVA therapy in hyperproliferative disorders include:

PUVA evokes immunological changes by affecting T lymphocytes and epidermal Langerhans cells.

It increases melanin in the skin and is therefore useful in treatment of vitiligo

It also inhibits mast cell release of inflammatory mediators

Formulations and dosage

 Methoxsalen is supplied in soft gelatin capsules  and hard gelatin capsules .

The dose is 0.4 mg/kg for the soft capsule and 0.6 mg/kg for the hard capsule taken 1.5–2 hours before UVA exposure.

A lotion containing 1% methoxsalen  also is available for topical application.

It can be diluted for use in bath water to minimize systemic absorption.

The risk of phototoxicity is increased with topical PUVA therapy.

Relapse occurs within 6 months of cessation of treatment in many patients, which has prompted efforts to design maintenance protocols.

Therapeutic uses

PUVA  is used to repigment the leukoderma of vitiligo.

Success rates are highest in young individuals with recent onset of disease involving nonacral areas.

Localized vitiligo can be treated with topical PUVA and more extensive disease with systemic administration.

PUVA also is employed in the treatment of cutaneous T-cell lymphoma, atopic dermatitis, alopecia areata, lichen planus, urticaria pigmentosa, and as a preventive modality in some forms of photosensitivity.

Toxicity and monitoring

 The major acute side effects of PUVA include nausea, blistering, and painful erythema.

PUVA-induced redness and blistering generally peak within 48–72 hours.

Chronic PUVA therapy accelerates photoaging and the development of actinic keratoses, nonmelanoma skin cancer, and melanoma.

Squamous cell carcinomas occur at 10 times the expected frequency.

In patients receiving 250 or more treatments, there is an increased risk of melanoma.

Careful monitoring of patients for cutaneous carcinoma therefore is essential.

ii. Photopheresis 

Extracorporeal photopheresis (ECP) is a method in which blood is treated with photoactive drugs which are then activated with UV light.

After oral administration of methoxsalen, leukocytes are separated from whole blood and then exposed to UVA radiation.

The irradiated cells then are returned to the patient.  

This method is used in the treatment of cutaneous T-cell lymphoma.

Mechanism of action

Following photoactivation, methoxsolaren binds irreversibly to both strands of  the DNA in nucleated cells.

This leads to apoptosis of the treated T-cells and may cause preferential apoptosis of damaged or abnormal T-cells thus targeting the pathogenic cells of cutaneous T-cell lymphoma.

In addition, ECP also induces  monocytes to differentiate into dendritic cells which are capable of phagocytosing and processing of the apoptotic T-cell antigens.

When these activated dendritic cells are re-infused into the patient , they cause a T-lymphocyte mediated immune response to the processed apoptotic T-cell antigens.

iii. Photodynamic therapy (PDT)

Porphyrins are potent photosensitizing intermediates in heme synthesis and have been found to accumulate in malignant cells.

This feature is used in photodynamic therapy in which a synthetic porphyrin is administered and the patient is exposed to visible light. 

The concept is based on the fact that tumor tissue selectively absorbs greater amounts of porphyrins than surrounding nontumor tissue.

The agents most widely employed in photodynamic therapy (PDT) are porphyrins, their precursors or derivatives.

Photodynamic therapy is used in the treatment of various dermatological disorders, particularly nonmelanoma skin cancer and precancerous actinic keratoses.

Mechanism of action

The photosensitized chemical reaction is oxygen-dependent.

Light delivered to the skin is absorbed by porphyrin molecules.

These molecules transfer their energy to oxygen, forming reactive oxygen species that result in injury or destruction of lipid-rich membranes and subsequent tissue damage.

PDT: D-aminolevulinic acid (d-ALA)

Early studies with PDT employed complex mixtures of poorly defined porphyrins known as hematoporphyrin derivative (PHOTOFRIN I) or a partially purified mixture known as porfimer sodium (PHOTOFRIN II) that was administered parenterally with subsequent irradiation using polychromatic light sources.

The major problem with this approach was the prolonged period (4–6 weeks) of photosensitivity caused by skin retention of the porphyrin formulations.

This led to a search for compounds that could be administered topically and that were eliminated more readily from the skin.

PDT: D-aminolevulinic acid (d-ALA)

The porphyrin precursor d-aminolevulinic acid (ALA) is converted to various porphyrins, particularly protoporphyrin (PROTO), in tissues including the skin.

Protoporphyrin subsequently is eliminated rapidly from the body, thereby minimizing the period of skin photosensitivity to a few hours.

Topically applied ALA HCl (20% w/v) and  the methyl ester of ALA have been used successfully for the PDT of various types of nonmelanoma skin cancers and premalignant lesions.

PDT: Therapeutic uses

Incoherent (nonlaser) and laser light sources have been used for PDT.

 The wavelengths chosen must include those within the action spectrum of protoporphyrin and ideally those that permit maximum skin penetration.

Light sources in use emit energy predominantly in the blue portion (maximum porphyrin absorption) or the red portion (better tissue penetration) of the visible spectrum.

Nonhypertrophic actinic keratoses and superficial basal cell carcinomas and Bowen’s disease seem to respond best to PDT.