592 Current Drug Metabolism, 2008, 9, 592-597 1389-2002/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Decreasing Systemic Toxicity Via Transdermal Delivery of Anticancer Drugs Jia-You Fang 1 , Pei-Feng Liu 2,3 and Chun-Ming Huang 2,3,4,* 1 Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Kweishan, Taoyuan, Taiwan; 2 VA San Diego Healthcare Center, San Diego, CA, USA; 3 Division of Dermatology, Department of Medicine; and 4 Moores Cancer Center; University of California, San Diego, USA Abstract: When used at a high dose, many anticancer drugs produce undesirable side effects including hepatotoxicity. Transdermal de- livery bypasses first-pass metabolism, allowing the use of a lower dose of drug while decreasing systemic toxicity. In this review, we summarize various advanced technologies for improving anticancer drug delivery via the skin. This technology is discussed in the con- text of three anticancer drugs, 5-fluorouracil (5-FU), methotrexate (MTX) and 5-aminolevulinic acid (5-ALA). The use of a erbium:YAG (Er:YAG) laser for transdermal delivery of anticancer drugs is specifically highlighted in this review. Keywords: Toxicity, transdermal delivery, laser, anticancer drugs. SYSTEMIC TOXIC EFFECTS OF ANTICANCER DRUGS Localized tumors are generally surgically removed, but patients face the risk of recurrent tumorigenesis unless systemic che- motherapies are used post-surgery. However, these systemic treat- ments can cause various widespread toxicities such as bone marrow suppression, cardiomyopathy, and neurotoxicity [1]. Moreover, high-dose chemotherapeutic agents often cause liver function ab- normalities and liver injury in cancer patients [2]. For instance, it has been reported that the use of chemotherapeutic agents including taxanes, oxaliplatin, irinotecan [3, 4] as well as anthracyclines [5] can result in hepatotoxicity. Furthermore, hepatic injury has been observed in colon cancer patients undergoing resection of hepatic metastases following chemotherapy [6]. Some anticancer drugs are also associated with hepatic veno- occlusive disease (VOD), which can damage hepatocytes. For ex- ample, high-doses of chemotherapy agents employed with hematopoietic stem cell transplantation in leukemia patients have been shown to cause VOD [7]. Additionally, it has been reported that VOD is induced by dacarbazine in murine liver cells [8]. Also, high doses of busulfan in adults receiving bufulfan/cyclophos- phamide regimens, and high doses of irradiation in cyclophos- phamide/ total-body irradiation regimens, can eventually lead to the development of severe VOD [9]. Finally, a number of observations also strongly suggest that actinomycin-D is the most likely cause of VOD in Wilms’ tumour [10]. Anticancer drugs can also cause liver cancer. Patients treated with tamoxifen have an increased risk of developing hepatic ade- nomas and hepatocellular carcinomas [11]. In addition, cyproterone acetate dose is correlated with increased mutation frequency in rat liver, causing tumorigenesis and mitogenesis [12]. Other in vitro studies have also demonstrated that anticancer drugs cause hepato- toxicity. 6-mercaptopurine, for example, is toxic to rat hepatocyte cultures via a mechanism that causes oxidative stress, mitochondrial injury and ATP depletion [13]. Moreover, another anticancer drug, flutamide, is toxic to human hepatocytes [14]. Numerous mechanisms have been proposed to explain the hepa- totoxicity associated with anticancer drugs. In the case of cyclo- phosphamide, one explanation is that the metabolism of the drug to acrolein and 4-hydroperoxycyclophosphamide causes toxicity to the hepatocytes [15]. Alternatively, the toxicity of busulfan is due to the conjugation of glutathione S transferase to glutathione, which leads to oxidative stress in cultured murine hepatocytes [16]. Pre *Address correspondence to this author at the Department of Medicine, Division of Dermatology, University of California, San Diego, Rm2317A, 3350 La Jolla Village, San Diego, CA, 92161, USA; Tel: 858-552-8585 ext 3708; Fax: 858-642-1435; E-mail: chunming@ucsd.edu clinical toxicological studies in mice, rats, dogs, monkeys and hu- mans have also contributed to our understanding of this toxicity by revealing a mechanism of hepatotoxicity of trabectedin, involving the activation of liver enzymes including bilirubin, alkaline phos- phatase, aspartate aminotransferase, and alanine aminotransferase [17]. Treatment of hepatocytes with flutamide or its major metabo- lite, 2-hydroxyflutamide, also induced robust toxicity, by inhibiting protein synthesis [14]. Moreover, a combination treatment using both flutamide and 2-hydroxyflutamide caused an additive toxic effect [14]. Additionally, it has also been previously shown that the cytotoxicity of 14 p-benzoquinone congeners to primary rat hepato- cyte resulted from the formation of reactive oxygen species and the depletion of glutathione [18]. Finally, the hepatotoxicity of ral- titrexed, an antimetabolite drug used in cancer chemotherapy, was primarily attributed to a transient and self-limiting increase in the level of transaminase [19]. Clinical pharmacokinetics, anticancer activities, and toxicities of other anticancer drugs, such as 5-fluorouracil (5-FU), metho- trexate (MTX) and 5-aminolevulinic acid (5-ALA), have been ex- tensively investigated in the past [20, 21]. 5-FU is a chemical abla- tive agent that inhibits DNA synthesis, prevents cell proliferation, and causes tumor necrosis. Solution and cream formulations of 5% 5-FU administered twice daily for at least 6 weeks have been ap- proved by the Food and Drug Administration (FDA) in the treat- ment of basal cell carcinoma (BCC) when conventional methods are impractical [22]. Potential hepatotoxicity from hepatic artery infusion (HAI) with 5-FU and systemic hyperthermia was noted in an animal model [23]. The hepatotoxicity of HAI with 5-FU and fluorodeoxyuridine has also been indicated in extensive preclinical and clinical research [24, 25]. Furthermore, 5-FU used with folinic acid for HAI is hepatotoxic to patients [26]. MTX is a folic acid antagonist with anti-neoplastic activity. The association of MTX with acute and chronic liver damage has also been documented [27]. Acute elevations of hepatic enzyme levels and/or hyperbilirubinaemia have been detected in more than 50% of the patients treated with a high-dose of MTX [27]. Additionally, based on a large meta-analysis, patients with psoriasis and rheuma- toid arthritis have a 7% chance of progressing at least one histologic grade on liver biopsy for every gram of MTX taken [28]. Photody- namic therapy with 5-ALA has been used to treat solar keratoses, BCC, and squamous cell carcinoma. Unfortunately, treatment with 5-ALA is also associated with liver damage. A high dose of 5-ALA brings a potential risk of phototoxic liver damage during exposure to high intensity operating room lights for several hours [29]. Also, Bechara et al. demonstrated that 5-ALA produced reactive oxygen species during metal-catalyzed aerobic oxidation, and subsequently caused an iron-catalyzed calcium-dependent oxidative damage to the inner membrane of rat liver mitochondria [30]. Furthermore,