Original article
Altered expression of rb and p53 in uveal melanomas following plaque radiotherapy1,

https://doi.org/10.1016/S0002-9394(01)01362-9Get rights and content

Abstract

PURPOSE : To examine the expression of proteins in the Rb and p53 tumor suppressor pathways in uveal melanomas following plaque radiotherapy.

METHODS : Immunohistochemistry and cell culture studies. Immunohistochemistry for Rb, p16, cyclin D1, p53, HDM2, and Bcl-2 was performed on twelve eyes containing posterior uveal melanomas that were enucleated following plaque radiotherapy. Cell culture studies were performed in three cases.

RESULTS : The irradiated eyes were enucleated for radiation complications (five cases), local tumor recurrence (three cases), and other reasons (four cases). On histopathologic examination, all cases showed evidence of tumor cell loss. However, residual tumor cells were present in all cases, including those that were clinically regressed. Residual cells from three of the clinically regressed cases were cultured and demonstrated minimal cell division, marked cell death, and extensive chromosomal damage. Strong p53 staining was observed in six cases (50%) and was significantly associated with recent radiotherapy (P = .04). Abnormal cytoplasmic staining for Rb was observed in four cases (33%).

CONCLUSIONS : Plaque radiotherapy of uveal melanomas induces DNA damage, inhibits cell division, and promotes cell death. These changes may be due, at least in part, to induction of p53, which activates genes involved in both cell cycle arrest and apoptosis. Plaque radiotherapy can also cause alterations in the expression of Rb, but the significance of this finding will require further study.

Section snippets

Tumor samples

Nine eyes of nine patients were identified by computer search to have undergone enucleation for posterior uveal melanoma following 125I or 60Co plaque radiotherapy between 1993 and 2001 at the Washington University Medical Center. In addition, tumor tissue was obtained prospectively for use in cell culture and cytogenetic studies from three eyes in three additional patients who required enucleation following 125I plaque radiotherapy (none of these had clinical evidence of local tumor

Results

The study included twelve uveal melanomas that had been treated with 125I (11 cases) or 60Co (1 case) plaque radiotherapy and subsequently required enucleation due to radiation complications (5 cases), local recurrence (3 cases), postoperative infection (1 case), corneal opacity (1 case), periocular pain (1 case), and patient request (1 case) (Table 1). Histopathologically, variable loss of tumor tissue was evident in all cases, although residual tumor cells could be identified in all 12 cases

Discussion

A major goal of radiation oncology is to induce “reproductive cell death” by rendering tumor cells incapable of proliferation or metastasis and triggering sustained cell death that corresponds to the regression of the tumor mass that is observed clinically.10, 11 In this study, we provide evidence that reproductive death occurs frequently in uveal melanomas following plaque radiotherapy and we present initial insights into potential molecular mechanisms for this phenomenon.

We found residual

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    This work was supported by NIH grants K08 EY00382-01 and R01 EY13169-01. Dr. Harbour was supported by a Career Development Award from Research to Prevent Blindness, Inc.

    1

    The author has no proprietary interest in this study.

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