Conventional tumor promoters

IMMUNOMODULATORY BIOPHARMACEUTICALS ARE UNLIKELY TO BE CONVENTIONAL TUMOR PROMOTERS... 

In the classic model of initiation and promotion, conventional tumor promoters (CTP) inhibit the intracellular mechanisms that can eliminate the nascent clone, facilitate accumulation of the mutations necessary for full malignant transformation, or disrupt intercellular signaling [15], A classic example of a CTP is 12-O-tetradecanoylphorbol- l 3-acetate (TPA, also referred to as phorbol myristate acetate, PMA). The mechanisms proposed for CTP that are relevant for the tumor types associated with immunosuppression, such as nonmelanoma skin tumors and lymphomas, are listed in Table 27.3. The table is limited to mechanisms of promotion and does not include tumor initiation mechanisms, namely those that directly or indirectly damage DNA (e.g., free radicals mediated by metabolism of ethanol) [16] or are mechanisms of neovasularization (e.g., angiogenesis in response to UV-A and B) [17], The table also excludes mechanisms of CTP that have only been studied in the context of irrelevant tumors, such as TCDD in hepatocarcinogenesis [18],... 

TABLE 27.3 Mechanisms of conventional tumor promotion in neoplasms relevant to IMBPs... 

In vitro Systems Example for Conventional Tumor Promoters Reference Example for Atypical Tumor Promoters or Their Targets Reference... 

A replication-deficient adenovirus has been used to deliver a gene construct, which contains within its promoter region a radiation-responsive element. Upon irradiation with conventional doses of X rays, this construct initiates transcription of the gene coding for the toxic cytokine, tumor necrosis factor-a (35). The above is an exquisite example of how emerging delivery and gene therapies are fast blurring the distinction between an active and an excipient (Fig. 3D). 

Monoclonal antibody therapy is based on the ability to target markers and bind to cell membrane antigens with great specificity. Many times the enhanced specificity demonstrated toward the tumor antigens allows normal cells to be protected against harmful effects, unlike conventional chemotherapy. There are several mechanisms by which monoclonal antibodies destroy or prevent further replication of malignant cells. Some monoclonal antibodies utilize tumor immunology and components of the host natural defense mechanism to exert their desired effect. For example, monoclonal antibodies can utilize tumor effector cells to promote tumor cell lysis or have the ability to directly modulate tumor function. 

A precise and concerted interplay between both the cellulcir components, i.e., the cells and their mutations, tmd the acellular components, i.e., the tumor microenvironment, drives tumor growth md spread beyond physiological boundaries as well as promotes cellular resistance to conventional radiotherapy and chemotherapy. 

Beyond these cellular factors, the acellular elements complementing the tumor as complex, autonomous tissues are increasingly identified as critical and potent carcinogenic promoters and modulators of tumor ceU sensitivity to conventional radiation and chemotherapies. The panel of acellular elements comprises, among others, soluble growth factors, oxygen, metabohtes, and the proteins of the extracellular matrix (ECM) (Cordes and Park 2007 Durand 1994 Kim etal. 2006 Petersen et al. 2003 Tannock 1996 Vaupel and Mayer 2005 Wedgwood and Younes 2006). 

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