The goal of this study is to determine whether treatment with methylselenocysteine (MSC) results in differential uptake of irinotecan and its active metabolite (SN-38) between tumors of head and neck squamous cell carcinomas and normal tissue. The in vivo synergy between MSC and irinotecan is influenced by treatment schedule and associated with enhancement of tumor vessel maturation, intra-tumor concentration of SN-38 and apoptotic death of tumor cells. Normal tissue drug concentrations of were not impacted by selenium treatment. The finding is of clinical relevance for enabling the delivery of higher doses of irinotecan to reverse tumor resistance, recurrence and ultimately enhancing cure rates. Introduction Irinotecan is a pro-drug that is activated by carboxylesterases into the active metabolite, SN-38 (7-ethyl-10-hydroxyl-camptothecin) [].

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Irinotecan treats multiple solid tumors [] by targeting topoisomerase I and resulting in double-stranded DNA breaks []. Methylselenocysteine (MSC) is a selenium containing compound that is activated by β-lyase into the active metabolite methylselenol []. MSC has modest partial response of anti-tumor activity when given alone. However, MSC enhances the anti-tumor activity (cure rates) of irinotecan against FaDu and A253 xenografts []. FaDu and A253, head and neck squamous cell carcinomas (HNSCC), were previously characterized [].

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FaDu is poorly differentiated and p53 mutant. A253 is well differentiated and null p53. Both untreated tumors have similar level of carboxylesterase-2, irinotecan activating enzyme [].

In nude mice bearing human FaDu xenografts, sequential combination treatment of MSC (0.2mg/d × 28) and irinotecan (100mg/kg/wk × 4) increased the complete response (CR) rate from 30% after irinotecan alone to 100% after the combination treatment []. The CR rate increased from 10% after irinotecan alone to 60% after the combination treatment in mice bearing A253 xenografts. Treatment with MSC alone resulted in 30% partial response (PR) but 0% CR.

Optimal therapeutic selectivity is achieved only when MSC is administered at least 7 days prior to irinotecan and continued throughout treatment schedule []. In our previously published study [], we demonstrated that the enhanced CR rates of HNSCC xenografts after combination treatment of MSC and irinotecan were due to multi-factorial alterations. Collectively, the shared changes in both xenografts after the first course treatment of irinotecan alone or in combination translated into increased intra-tumor SN-38 concentration []. Based on these findings, we designed this study to address the following questions: (i) Does MSC administered concurrently with irinotecan alter plasma and intra-tumor concentrations of irinotecan and SN-38? (ii) What is the effect of adding MSC on concentrations of irinotecan and SN-38 after the second course of irinotecan treatment?

(iii) What is the effect of adding MSC on normal tissue concentrations of irinotecan and SN-38? (iv) What is the effect of adding MSC on tumor microvessel maturation? (v) What is the effect of adding MSC on apoptotic cell death? The answers to these questions are critical to confirm whether giving MSC sequentially alters SN-38 intra-tumor concentration but does not affect its normal tissue concentration. In this study using our preclinical xenografts models, we confirmed that the increase in vessel maturation and drug concentration needed at least 15 days to be achieved, which resulted in an increase in apoptotic cell death. Thus, the increase of anti-tumor selectivity and activity by adding MSC might be due in part to the increase of the intra-tumor drug availability, thus SN-38 binds more to its target and produces more cell death.

Tumors transplantation FaDu and A253 cell lines were purchased from American Type Culture Collection (Rockville, MD), and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (GIBCO BRL, Life Technologies, Grand Island, NY). Cell lines were tested every two months for mycoplasma using Mycoplasma T. Rapid Detection System (Gen-Probe Inc., San Diego, CA). Human HNSCC xenografts were initially established by implanting 10 6 cultured cells subcutaneously into female athymic nude mice (nu/nu) from Harlan Sprague-Dawley, Inc. (Indianapolis, IN).

Xenografts were passed several generations by transplanting ~ 50mg non-necrotic tumor tissues before treatment. FaDu and A253 tumors were implanted bilaterally to eliminate host variability. Mice were housed 5 per cage under specific pathogen-free conditions following an institutionally-approved protocol. Drugs and treatments Irinotecan was purchased from Pfizer Pharmacia Upjohn Corporation (New York, NY), as a ready-to-use clinical formulation solution.