Bcl-2 and Bax Expression Predict Prostate Cancer Outcome in Men Treated with Androgen Deprivation and Radiotherapy on Radiation Therapy Oncology Group Protocol 92-02

Abstract

Purpose: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another RadiationTherapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT). Experimental Design: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure. Results: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT. Conclusions: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.

Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer With Respect to the Outcome of Radical Radiotherapy Dose Escalation

“…Several previous studies have analyzed prostate cancer radiotherapy outcome with respect to tumor Bcl-2 expression, and most (21,25,26,28) but not all (27) have observed an association between Bcl-2 overexpression and adverse disease control. Much the largest study is that by Khor et al Abbreviations: HR = hazard ratio; CI = confidence interval; PSA = prostate-specific antigen; RT = radiation therapy.…”

“…Treatment with either antisense Bcl-2 (19) or a small molecule inhibitor of Bcl-2 (20) has been shown to sensitize prostate cancer cells to radiation. Some (21)(22)(23)(24)(25) but not all (26)(27)(28) studies have observed an association between Bcl-2 expression and adverse outcomes from radical treatment of localized prostate cancer. p53 is known to be a key mediator of apoptotic cell death in response to DNA-damaging agents such as radiation (29).…”

Quantitative Analysis of mRNA for 10 Different Drug Resistance Factors in Dogs with Lymphoma

“…Over-expression of transport proteins including P-glycoprotein (P-gp) (the product of ABCB1, formerly called MDR1 gene [28]), multidrug resistance-associated protein 1 (MRP1) (the product of ABCC1 gene [28]), lung resistance-associated protein (LRP) [14], and breast cancer-resistant protein (BCRP) (the product of ABCG2 gene [5]) is known to be the major mechanism of reduced drug accumulation. Mechanisms of decreased apoptosis include aberrant of p53 gene and overexpression of Bcl-2 [4,16,19,27]. Wild-type P53 has many functions, such as induction of a transient (cell cycle arrest) or permanent (senescence) blockage of cell proliferation and the activation of cell death pathways in response to genotoxic stress (apoptosis).…”

Main Pro-Apoptotic Member of Bcl-2 Family Proteins – Bax

“…For instance, the cellular level of Bax and Bcl-2 proteins in prostate cancer cells is a predictive factor forecasting the result of the therapy based on androgen deprivation and radiation (KHOR et al 2007). It has been also shown that Bax/Bcl-2 rate in chronic lymphocytic leukemia (CLL) inversely correlates with resistance of leukemic cells to cytotoxic drugchlorambucil in vitro as well as with clinical responsiveness (PEPPER et al 1997).…”