Progress in Cancer Chemoprevention

Abstract

More than 40 promising agents and agent combinations are being evaluated clinically as chemopreventive drugs for major cancer targets. A few have been in vanguard, large-scale intervention trials--for example, the studies of tamoxifen and fenretinide in breast, 13-cis-retinoic acid in head and neck, vitamin E and selenium in prostate, and calcium in colon. These and other agents are currently in phase II chemoprevention trials to establish the scope of their chemopreventive efficacy and to develop intermediate biomarkers as surrogate end points for cancer incidence in future studies. In this group are fenretinide, 2-difluoromethylornithine, and oltipraz. Nonsteroidal anti-inflammatories (NSAID) are also in this group because of their colon cancer chemopreventive effects in clinical intervention, epidemiological, and animal studies. New agents are continually considered for development as chemopreventive drugs. Preventive strategies with antiandrogens are evolving for prostate cancer. Anti-inflammatories that selectively inhibit inducible cyclooxygenase (COX)-2 are being investigated in colon as alternatives to the NSAID, which inhibit both COX-1 and COX-2 and derive their toxicity from COX-1 inhibition. Newer retinoids with reduced toxicity, increased efficacy, or both (e.g., 9-cis-retinoic acid) are being investigated. Promising chemopreventive drugs are also being developed from dietary substances (e.g., green and black tea polyphenols, soy isoflavones, curcumin, phenethyl isothiocyanate, sulforaphane, lycopene, indole-3-carbinol, perillyl alcohol). Basic and translational research necessary to progress in chemopreventive agent development includes, for example, (1) molecular and genomic biomarkers that can be used for risk assessment and as surrogate end points in clinical studies, (2) animal carcinogenesis models that mimic human disease (including transgenic and gene knockout mice), and (3) novel agent treatment regimens (e.g., local delivery to cancer targets, agent combinations, and pharmacodynamically guided dosing).

Induction of DT-diaphorase by 1,2-dithiole-3-thiones in human tumour and normal cells and effect on anti-tumour activity of bioreductive agents

“…The enzyme has also been shown to play an important role in detoxifying chemically reactive metabolities in cells, thus protecting the cell from their toxic and mutagenic effects (Beyer et al, 1988;Riley and Workman, 1992). Recent studies have investigated the use of inducers of DTdiaphorase in cancer prevention (Kelloff et al, 1990;Kensler et al, 1992;O'Dwyer et al, 1996). However, there have been few investigations of the potential use of inducers of DT-diaphorase to enhance the anti-tumour activity of anti-tumour agents that are activated by this enzyme.…”

“…DTdiaphorase is induced in many tissues by a wide variety of structurally dissimilar chemicals, including 1,2-dithiole-3-thiones (D3Ts), quinones, diphenols, phenylenediamines, Michael reaction acceptors, isothiocyanates and heavy metals (Prestera et al, 1993). Thus, studies have investigated the use of inducers of DTdiaphorase and other phase II detoxifying enzymes in cancer prevention (Kelloff et al, 1990; Kensler and Helzlsouer, 1995). Oltipraz, a D3T analogue used for treatment of schistosomiasis (Bueding et al, 1982), is an inducer of phase II detoxifying enzymes (Kensler et al, 1992;Egner et al, 1994;Kensler and Helzlsouer, 1995) and inhibits development of tumours in animals (Kelloff et al, 1990; Kensler et al, 1992; Kensler and Helzlsouer, 1995).…”

“…Thus, studies have investigated the use of inducers of DTdiaphorase and other phase II detoxifying enzymes in cancer prevention (Kelloff et al, 1990; Kensler and Helzlsouer, 1995). Oltipraz, a D3T analogue used for treatment of schistosomiasis (Bueding et al, 1982), is an inducer of phase II detoxifying enzymes (Kensler et al, 1992;Egner et al, 1994;Kensler and Helzlsouer, 1995) and inhibits development of tumours in animals (Kelloff et al, 1990; Kensler et al, 1992; Kensler and Helzlsouer, 1995). This agent has low toxicity in animals and is in phase I and II clinical trials as a chemoprotective agent in humans (Kensler et al, 1992;Maxuitenko et al, 1996;O'Dwyer et al, 1996).…”

Glycemic index in chronic disease: a review

“…Tamoxifen is used in the prevention and therapy of breast cancer and has been found to reduce serum levels of IGF-1 and raise IGFBP-1 in postmenopausal breast cancer patients (Ho et al, 1998). This has been proposed as one of the mechanisms through which the antiestrogenic drug tamoxifen and more recently fenretinide, a vitamin A analog, may inhibit growth of mammary tumor cells (Ho et al, 1998;Kelloff et al, 1999). Epidemiologic evidence is suggesting a possible role of IGFs in promoting and IGFBPs in suppressing breast carcinogenesis.…”

Prostate cancer chemoprevention agents exhibit selective activity against early stage prostate cancer cells

“…10 This problem is compounded when one is considering an early intervention/ chemoprevention strategy. 11 This is because endpoints for chemoprevention trials differ from those sought in more conventional clinical trials which seek to accrue a cohort of patients with advanced disease.…”