Androgen ablation therapy has been an important modality for the treatment of disseminating prostatic cancer for nearly 60 years. Unfortunately, when given alone, such therapy is rarely curative. The failure of this therapy to cure prostate tumors, even though it can induce an initially positive response, is not the result of a change in the systemic effectiveness of such treatment. Instead, the development of resistance to therapy is related to changes in the tumor. Experiments by a large number of investigators have identified several of the important tumor cell and host factors involved in these changes. Through the identification of these factors, the concept has evolved that there may be multiple pathways for the development of resistance to hormonal therapy based on a stem cell model for the normal prostate. Although such pathways can be described in phenomenological terms, the detailed molecular biology of such a process is still unknown. The essential feature of the development of androgen resistance is the emergence of androgen-independent or sensitive cancer cells. The critical question for that must be answered by future studies is exactly how such androgen-independent cells develop. An explanation may make it possible to design therapies to prevent the development of these independent tumor cells. Under such conditions, androgen ablation therapy used as a single modality could become potentially curative. Even if therapeutic means can be developed to prevent the emergence of androgen- independent or sensitive tumor cells, to be effective, this type of blocking therapy would have to be performed before such development had already occurred. Therefore, before such therapy is begun, some type of clinical test would be required to determine that the tumor did not already have some androgen-independent or sensitive tumor cells present (i.e., the tumor was not already heterogeneous androgen-sensitive). Because, currently, neither a method for determining the homogeneous versus heterogeneous nature of the androgen requirements of a particular tumor nor a method for the prevention of the development of androgen-independent or sensitive tumor cells from dependent prostate cancer cells is available, these should be critical areas for extensive future study. Any advancement in either of these areas would have profound consequences on the more effective issue of androgen ablation therapy. Until these advancements are made, androgen ablation therapy can be used in combination with other modalities of treatment (e.g., radiation and chemotherapy), which are specifically targeted at the androgen-independent or sensitive cells either initially present or developing during androgen ablation therapy. Standard antiproliferative chemotherapeutic agents may be ineffective against such androgen-independent or sensitive prostatic cancers because these cancers have a low proliferative rate. Berges and co-workers demonstrated that the median daily proliferative rate of prostate cancer cells within lymph nodes or bone metastases was less than 3.0% per day. Newer agents are needed to target the greater than 95% of prostate cancer cells within a given metastatic site that are not immediately proliferating. One such approach that has been recently proposed is the use of potent and selective inhibitors of the endoplasmic reticulum Ca2+ ATP-dependent pump. In such combination approaches, it will be critical to evaluate the importance of both the timing (early versus late) and the order (sequential versus simultaneous) of androgen therapy in relation to the other modalities used.
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