Introduction

From the early development of chemotherapeutic drugs and their application in the treatment of cancer significant advances have resulted on the underlying molecular mechanisms of their mode of cytotoxic action and the biology of cancer diseases. Although treatment with chemotherapeutic drugs resulted in significant clinical responses and overall survival, there remains the problem of the development and/ or acquisition of tumor resistance to chemotherapy [1]. The failure to eradicate resistant tumors to conventional therapeutics has led to the introduction of immu-notherapy. In practice, tumor immunotherapy is an ideal therapeutic approach because it offers several advantages over chemotherapy including low organ toxic-ity and high tumor selectivity. In immunotherapy, cytotoxic cells are derived from the host's own immune system such as lymphokine-activated killer (LAK) cells and interleukin 2 (IL-2)-activated tumor infiltrating lymphocytes (TIL) [2]. Also, based on the principle that most tumors have the capacity to trigger an immune response, immunotherapy can be used for the selective and specific recognition of tumor targets by the generation of specific antitumor cytotoxic T-cell responses [3]. There is a prevalent dogma that immunotherapeutic strategies under investigation can conquer chemoresistant tumors and assume that immunotherapy attacks tumor cells by different mechanisms of action than those achieved by chemotherapeutic drugs and may not be subjected to the same mechanisms underlying drug resistance. Despite the proposed advantages over chemotherapy, immunotherapy today fails to deliver a significant curative rate. Initially, immunotherapy or T-cell based immunotherapeutic approaches (e.g. LAK and TIL) have generated a great deal of excitement when they were shown to be effective in certain transplantable tumors in mice [4]. Subsequent studies with the LAK or TIL systems in clinical trials in patients with advanced diseases failed to demonstrate a significant clinical response rate [5]. Further, studies with cytokine gene transfer into tumor targets and pulsing CTLs with specific tumor peptides (that is tumor vaccines) still proved to be unsuccessful in long term cures as well [6,7]. Clearly, T-cell based immunotherapy has its own limitations. The lack of significant positive response by immunotherapy against drug resistant tumor cells suggests that the mere manipulation of the immune system may be not sufficient to restore a positive antitumor killing. Other aspects such as tumor manipulation of neo-antigens, MHC-1, suppressive factors, etc. might be involved in the failure to respond to immunotherapy. However, one aspect that has not been seriously considered is the tumor cell sensitivity to killing by cytotoxic lymphocytes and the development of resistance to killing by the cyto-toxic lymphocytes. It is unclear if drug resistant tumors are initially sensitive to killing mediated by cytotoxic lymphocytes. It is possible that the poor effectiveness of immunotherapy is that, although immune cells could recognize chemoresistant tumors, chemoresistant tumors are also equally resistant to immune-mediated killing mechanisms. It follows that chemoresistant tumors are also equally resistant to immune-mediated killing mechanisms. Thus, the success of immunotherapy will ultimately be dictated by both the presence of antitumor CTLs and the sensitivity of tumor targets to the killing mediated by these cells. In addition, tumor chemore-sistance may reflect an important part of the general tumor resistant mechanism to a common cytotoxic pathway mediated by various stimuli, namely apoptosis or programmed cell death, and such resistant scheme to a central cytotoxic pathway may also render the cells resistant to immune-mediated killing [8]. The definition of cross-resistance actually could go beyond the multi-drug resistance phenomena and encompasses other cytotoxic stimuli including the cytotoxic immune cells. Therefore, the ultimate goal for a successful antitumor therapy, be with chemotherapy, radiation, or immunotherapy is to overcome cross-resistance for the ultimate induction of apoptosis. Many physiological and external stimuli can induce apop-tosis in susceptible cells including both chemotherapeutic drugs and host activated immune cells. However, not all tumor cells are intrinsically sensitive to apoptosis and most malignant cells develop resistance to apoptosis by dysregulating the apoptotic pathways that are triggered by drugs and immune cells. With the premise that chemoresistant tumors develop general mechanisms of resistance to apoptosis-mediated stimuli, our hypothesis and reported studies put forth are that for an effective antitumor therapeutic strategy it is essential to utilize complimentary pro-apoptotic signals to overcome tumor resistance to immune-mediated apoptosis.

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