Thiouracil Distribution in Mice Carrying Transplantable Melanoma1

Data published by others have shown that thiouracil (TU) is taken up selectively during melanin synthesis following trace doses of labeled TU. The concentration in newly forming mel anin has been attributed to the incorporation of TU as a "false precursor" in the biosynthetic pathway of melanin. Information made available previously has been in terms of relative values in various tissues rather than absolute concentration of TU per g wet weight of tissue. The latter parameter is essential for evaluation of absorbed dose from radiation and thus the ther apeutic potential of 3SSor 14C-labeled TU. The experiments described in this paper present the absolute uptake of TU in Harding-Passey melanoma and other normal tissues in BALB/c mice. TU concentration was correlated with melanin content, and results were extrapolated to levels of pigmentation found in human melanoma. Uptake of TU was measured as a function of time following trace, medium, and high doses (mul tiple doses of 25 ¡igTU per g body weight). We found that the uptake of [14C]TU in tumor is high (9 to 12% of injected dose per g of tumor) and that tumornormal tissue concentration ratios varied from 50:1 in metabolizing organs, such as lung and liver, to 80:1 in pigmented whole eye and 300:1 in such tissues as muscle and brain. Little change in the percentage of uptake was noted, as administered dose was increased by 5000 times. At the highest doses of TU delivered, 300 /ig TU were incorporated per g tumor. At specific activities of [35S]TU available commercially, this would result in a dose of about 20 rads/hr, which is well within the range used for permanent implant therapy. Thus, the possibility exists that primary and metastatic melanoma can be targeted on a cellular level and that cytotoxic doses can be delivered while limiting normal tissue doses to no greater than about 2% of tumor dose. The targeting of TU to melanoma is analogous to that of iodine to thyroid. This unique selectivity may allow systemic application of radiolabeled TU for therapy and diagnosis of melanoma without undue harm to or interference from normal tissues.