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Release of doxorubicin in sweat: first step to induce the palmar-plantar erythrodysesthesia syndrome?

2005; Elsevier BV; Volume: 16; Issue: 7 Linguagem: Inglês

10.1093/annonc/mdi204

1569-8041

U. Jacobi, Evguenia Waibler, P Schulze, Jalid Sehouli, G. Oskay-Özcelik, Tobias Schmook, Wolfram Sterry, Jürgen Lademann,

Cancer and Skin Lesions

Doxorubicin, one of the most potent single chemotherapeutic agents against solid and angiomatous tumors, is encapsulated in highly stable Stealth® liposomes so that its toxicity is significantly reduced [1.Berry G. Billingham M. Alderman E. et al.The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin.Ann Oncol. 1998; 9: 711-716Abstract Full Text PDF PubMed Scopus (227) Google Scholar]. The efficacy and toxicity of doxorubicin is affected by the different liposomal leakage rates; liposomes with the slowest rate of drug leakage showed the best therapeutic activity [2.Charrois G.J. Allen T.M. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer.Biochim Biophys Acta. 2004; 1663: 167-177Crossref PubMed Scopus (256) Google Scholar]. Nevertheless, severe and dose-limiting mucocutaneous reactions occur [3.Lotem M. Hubert A. Lyass O. et al.Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin.Arch Dermatol. 2000; 136: 1475-1480Crossref PubMed Scopus (169) Google Scholar], mostly the palmar-plantar erythrodysesthesia syndrome (PPE). This syndrome is mainly located on the palms and plantae, but it may also affect intertrigeneous sites. A better understanding of the pathogenesis of PPE could provide the basis for its prevention and effective treatment.Fifteen patients were observed for six cycles of their therapy with encapsulated doxorubicin (Caelyx, Essex Pharma GmbH, Munich, Germany) against carcinoma. Cutaneous side-effects that occurred during this period were documented (Table 1). Five women, who discontinued treatment for unknown reasons, were excluded from the study. Five patients developed PPE, mainly localized on the palms and plantae. These patients also demonstrated palmar and plantar hyperhidrosis (5 from 5 and 4 from 5, respectively). The two patients with PPE with a high grade 3 developed PPE on intertrigeneous sites, i.e. the axilla. Toxic effluvium (n = 4) and atopic eczema (n = 2) were also observed.Table 1Clinical characteristics of patients undergoing therapy with encapsulated doxorubicinPatientno.SexAge(years)DiagnosisCaelyx dose (mg/m2)Localization of PPEPPE grade [3.Lotem M. Hubert A. Lyass O. et al.Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin.Arch Dermatol. 2000; 136: 1475-1480Crossref PubMed Scopus (169) Google Scholar]Onset of PPE after commencement of therapy (days)Localization of hyperhidrosisOther cutaneous side-effects1F61OC (R), lymph node metastasis20 (2 weeks)P, S, A321P, S, AToxic effluvium, atopic eczema (P)2F45OC25 (2 weeks)P, S, A, décolleté, groin321P, A–3F65OC (R)25 (2 weeks)P, S158P, S, AAtopic eczema (breast)4F62OC (R)20 (2 weeks)P, S121P, SToxic effluvium5F39OC (R)25 (2 weeks)P, S158P, S–6F62OC (R)20 (2 weeks)–––AToxic effluvium7F59OC20 (2 weeks)–––––8F55OC (R)20 (2 weeks)–––AToxic effluvium9F59OC20 (2 weeks)–––A–10M53Metastasized squamous cell carcinoma20 (4 weeks)–––––OC, ovarian carcinoma; R, recurrent; P, palm; S, sole; A, axilla. Open table in a new tab In addition, the fluorescence of the drug was qualitatively determined in vivo in the uppermost part of the skin using a dermatological laser scanning microscope (Stratum, Optiscan Ltd., Melbourne, Australia) [4.Jacobi U. Waibler E. Bartoll J. et al.In vivo determination of doxorubicin and its metabolites within the skin using laser scanning microscopy.Laser Phys Lett. 2004; 1: 100-104Crossref Google Scholar]. The measurements were performed on a male patient (no. 10) before and after intravenous treatment of the flexor forearm, the palm, the sole, the axilla and the forehead.Three hours after injection, fluorescence was detected on the skin surface of all sites and in the uppermost part of the skin on the plantae and palms. The fluorescence signal on the palm was detected deep in a sweat duct (Figure 1A) and around its opening in the upper skin layers (Figure 1B).The observed results indicate a possible relationship between the hyperhidrosis on the palms and plantae and the development of PPE on these skin sites during therapy. Both skin sites are characterized by the highest number of eccrine sweat glands which continuously excrete serous fluid [5.Sato K. Leidal R. Sato F. Morphology and development of an apoeccrine sweat gland in human axillae.Am J Physiol. 1987; 252: R166-R180PubMed Google Scholar]. Similar apoeccrine and eccrine sweat glands are located in the axillae [5.Sato K. Leidal R. Sato F. Morphology and development of an apoeccrine sweat gland in human axillae.Am J Physiol. 1987; 252: R166-R180PubMed Google Scholar], which are also frequently affected by PPE. Indeed, the drug was observed in the sweat inside the excretory ducts of sweat glands (Figure 1A). This result indicates that the sweat functions as a carrier of doxorubicin to the skin surface, presumably favoured by the hydrophilic coating of the liposomes. After excretion on the skin surface, the sweat containing the drug may penetrate into the stratum corneum (Figure 1B). The stratum corneum could be functioning as a reservoir for the penetration of doxorubicin into deeper skin layers, where its radicals will be formed and react with epidermal cells.In conclusion, the induction of PPE during therapy with encapsulated doxorubicin could be avoided by the prevention of hyperhidrosis. Routinely used antihidrotic treatments, such as ionotophoresis or topically applied aluminum chloride, may help to reduce PPE and should be investigated in prospective trials. The reproducibility of the results obtained by laser scanning microscopy should also be investigated. Doxorubicin, one of the most potent single chemotherapeutic agents against solid and angiomatous tumors, is encapsulated in highly stable Stealth® liposomes so that its toxicity is significantly reduced [1.Berry G. Billingham M. Alderman E. et al.The use of cardiac biopsy to demonstrate reduced cardiotoxicity in AIDS Kaposi's sarcoma patients treated with pegylated liposomal doxorubicin.Ann Oncol. 1998; 9: 711-716Abstract Full Text PDF PubMed Scopus (227) Google Scholar]. The efficacy and toxicity of doxorubicin is affected by the different liposomal leakage rates; liposomes with the slowest rate of drug leakage showed the best therapeutic activity [2.Charrois G.J. Allen T.M. Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer.Biochim Biophys Acta. 2004; 1663: 167-177Crossref PubMed Scopus (256) Google Scholar]. Nevertheless, severe and dose-limiting mucocutaneous reactions occur [3.Lotem M. Hubert A. Lyass O. et al.Skin toxic effects of polyethylene glycol-coated liposomal doxorubicin.Arch Dermatol. 2000; 136: 1475-1480Crossref PubMed Scopus (169) Google Scholar], mostly the palmar-plantar erythrodysesthesia syndrome (PPE). This syndrome is mainly located on the palms and plantae, but it may also affect intertrigeneous sites. A better understanding of the pathogenesis of PPE could provide the basis for its prevention and effective treatment. Fifteen patients were observed for six cycles of their therapy with encapsulated doxorubicin (Caelyx, Essex Pharma GmbH, Munich, Germany) against carcinoma. Cutaneous side-effects that occurred during this period were documented (Table 1). Five women, who discontinued treatment for unknown reasons, were excluded from the study. Five patients developed PPE, mainly localized on the palms and plantae. These patients also demonstrated palmar and plantar hyperhidrosis (5 from 5 and 4 from 5, respectively). The two patients with PPE with a high grade 3 developed PPE on intertrigeneous sites, i.e. the axilla. Toxic effluvium (n = 4) and atopic eczema (n = 2) were also observed. OC, ovarian carcinoma; R, recurrent; P, palm; S, sole; A, axilla. In addition, the fluorescence of the drug was qualitatively determined in vivo in the uppermost part of the skin using a dermatological laser scanning microscope (Stratum, Optiscan Ltd., Melbourne, Australia) [4.Jacobi U. Waibler E. Bartoll J. et al.In vivo determination of doxorubicin and its metabolites within the skin using laser scanning microscopy.Laser Phys Lett. 2004; 1: 100-104Crossref Google Scholar]. The measurements were performed on a male patient (no. 10) before and after intravenous treatment of the flexor forearm, the palm, the sole, the axilla and the forehead. Three hours after injection, fluorescence was detected on the skin surface of all sites and in the uppermost part of the skin on the plantae and palms. The fluorescence signal on the palm was detected deep in a sweat duct (Figure 1A) and around its opening in the upper skin layers (Figure 1B). The observed results indicate a possible relationship between the hyperhidrosis on the palms and plantae and the development of PPE on these skin sites during therapy. Both skin sites are characterized by the highest number of eccrine sweat glands which continuously excrete serous fluid [5.Sato K. Leidal R. Sato F. Morphology and development of an apoeccrine sweat gland in human axillae.Am J Physiol. 1987; 252: R166-R180PubMed Google Scholar]. Similar apoeccrine and eccrine sweat glands are located in the axillae [5.Sato K. Leidal R. Sato F. Morphology and development of an apoeccrine sweat gland in human axillae.Am J Physiol. 1987; 252: R166-R180PubMed Google Scholar], which are also frequently affected by PPE. Indeed, the drug was observed in the sweat inside the excretory ducts of sweat glands (Figure 1A). This result indicates that the sweat functions as a carrier of doxorubicin to the skin surface, presumably favoured by the hydrophilic coating of the liposomes. After excretion on the skin surface, the sweat containing the drug may penetrate into the stratum corneum (Figure 1B). The stratum corneum could be functioning as a reservoir for the penetration of doxorubicin into deeper skin layers, where its radicals will be formed and react with epidermal cells. In conclusion, the induction of PPE during therapy with encapsulated doxorubicin could be avoided by the prevention of hyperhidrosis. Routinely used antihidrotic treatments, such as ionotophoresis or topically applied aluminum chloride, may help to reduce PPE and should be investigated in prospective trials. The reproducibility of the results obtained by laser scanning microscopy should also be investigated.