Current Cancer Therapy Reviews - Volume 1, Issue 3, 2005

The polyamines putrescine, spermidine, and spermine are small, aliphatic amines that play an important role in multiple cellular functions. Activation of the polyamine pathway is involved in carcinogenesis and other aspects of tumor biology including in breast cancer. Levels of ornithine decarboxylase (ODC), the first and rate-limiting enzyme in polyamine biosynthesis as well as the levels of polyamines, are higher in human breast cancer specimens than in normal and benign breast tissue. Inhibition of ODC with -difluromethylornithine exerts a protective effect in the promotion of chemically induced rat mammary tumors as well as in the development of breast cancers in a transgenic model system. Inhibition of polyamine biosynthesis has also been shown to inhibit the growth of hormone-dependent and -independent mammary tumors, both in vitro and in vivo, thus indicating a major role for polyamines in breast cancer cell proliferation. Several lines of evidence indicate that increased ODC activity may contribute to breast cancer progression. Increased tumor ODC activity has been shown to be an independent, adverse prognostic factor for overall survival in women with localized breast cancer. This finding suggests that polyamines may be critically involved in the development of breast cancer metastasis. We have, indeed, observed that administration of DFMO markedly reduced in vitro invasiveness of the hormone-independent MDA-MB-435 and MDA-MB-231 human breast cancer cell lines. More importantly, we have observed that DFMO administration significantly reduced the development of pulmonary metastasis from orthotopically implanted MDA-MB-435 breast cancer xenografts in nude mice. The mechanism of antitumor action of DFMO is currently under active investigation. Several laboratories have shown that inhibition of polyamine biosynthesis results in activation of the MAPK pathway and STAT signaling. We have recently shown that DFMO induced activation of the MAPK pathway in MDA-MB-435 human breast cancer cells is directly involved in the production of the anti-invasive protein, thrombospondin-1. Inhibition of MAPK phosphorylation suppressed DFMO-induced stimulation of thrombospondin-1 and reversed its anti-invasive effect. Collectively, these data indicate that the polyamine pathway may be an attractive target for breast cancer prevention and treatment.

Bisphosphonates have been widely used over the past decade to prevent skeletal complications in breast cancer patients with bone metastases. The skeletal complications associated with bone metastases include severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia. A number of bisphosphonates, including oral clodronate, intravenous (IV) pamidronate, IV zoledronic acid, and ibandronate have been shown to significantly reduce skeletal complications and palliate bone pain in patients with breast cancer based on placebo-controlled trials. However, only zoledronic acid and pamidronate have been directly compared within a single trial, and zoledronic acid (4 mg via 15- minute infusion) was shown to be significantly more effective than 90 mg pamidronate at reducing the overall risk of skeletal complications in patients with breast cancer. Both IV pamidronate and zoledronic acid are recommended by the American Society of Clinical Oncology for the treatment of malignant bone disease. As we look to the future, the role of bisphosphonates will continue to evolve beyond the prevention of skeletal complications. Encouraging results have recently been reported from studies assessing the effects of bisphosphonates on tumor progression in bone and for the prevention of cancer treatment-induced bone loss.

Pancreatic cancer is one of the most resistant cancers to conventional treatment modalities and is generally in the locally advanced or metastatic stage at the time of initial diagnosis. Approximately only 20% of patients are diagnosed as potentially resectable but 5-year survival rate is no more than 20-25% even in these resectable ones. Realizing the poor prognosis with a single-modality approach, several studies that used the combination of chemotherapy and radiotherapy with surgery are performed in order to improve local control and survival. This review evaluates the existing data and future aspects about the combined modality treatment in locally advanced pancreatic cancer regarding both the efficiency and toxicity of these combinations and novel agents.

The great success of all-trans-retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL) revolutionized the treatment of the disease and introduced the concept of differentiation therapy. ATRA, a physiologic derivative of vitamin A (retinol), induces complete clinical remissions (CR) in majority of patients with APL, M3 type of acute myeloid leukemia (AML). In contrast to the cytotoxic chemotherapeutics, ATRA can selectively induce terminal differentiation and apoptosis of leukemic cells without causing bone marrow hypoplasia or exacerbation of the frequently occurring fatal hemorrhagic syndromes in patients with APL. Despite the high remission rates of up to 90% with oral ATRA alone, these remissions are transient and seldom durable. Chronic daily oral administration of ATRA results in accelerated metabolism of ATRA, leading to a progressive decline in plasma drug concentrations. These lower drug levels are associated with relapses and resistance to oral ATRA. Thus oral ATRA has to be combined with cytotoxic chemotherapy. However, liposomal ATRA (L-ATRA) "monotherapy" induces long term (up to five years) molecular remissions (negative-PCR for PML-RARα) in about 40% of the newly diagnosed APL patients. This review discusses current basic, clinical knowledge and clinical experience with APL patients treated with L-ATRA and the possible impact of L-ATRA on the outcome of APL.

Cancer patients report widespread use of antioxidant supplements during chemotherapy, despite recommendations by the American Institute for Cancer Research and others that supplements should not be used during treatment. These guidelines are based upon the fact that numerous chemotherapeutic agents, as well as radiation therapy, exert their cytotoxic effects by generation of reactive oxygen species (ROS), which cause massive damage to DNA and proteins and trigger apoptosis, resulting in tumor and normal cell death. Thus, there is the concern that antioxidants may block the ROS-generated effects of therapy on tumor cells. There are no data based on sound epidemiological or clinical studies to support this hypothesis, however. In fact, some experimental studies have shown that antioxidants may potentiate the effects of chemotherapeutic drugs, while also lessening treatment-related toxicities. In this report, we review the literature regarding chemotherapy and radiation therapy as sources of oxidative stress, and present the current data regarding effects of antioxidant supplement use on normal and cancer cells. The role of antioxidant supplements, as well as the role of genetic variants in oxidative stress genes, in relation to cancer treatment toxicities and survival are discussed.

Inositol and its phosphorylated form - inositol hexaphosphate (IP6) are naturally occurring carbohydrates, abundantly found in certain high-fiber diets, such as cereals and legumes. They, as well as other inositol phosphates with fewer phosphate groups (IP1-5) are contained in almost all mammalian cells, although in much smaller amounts, where they are important in regulating vital cellular functions. A striking anticancer action of IP6 was demonstrated in different experimental models. Although inositol possesses a modest anticancer activity, the most consistent and best anticancer results were obtained from the combination of Inositol + IP6. In addition to reducing cell proliferation, IP6 increases differentiation of malignant cells, often resulting in reversion to normal phenotype with decreasing production of tumor markers such as CEA, PSAP, and AFP. Exogenously administered IP6 is rapidly taken into the cells and dephosphorylated to lower inositol phosphates, which further affect signal transduction pathways resulting in cell cycle arrest. Enhanced immunity and antioxidant properties also contribute to tumor cell destruction. Because it is abundantly present in regular diet, efficiently absorbed from the gastrointestinal tract, and safe, Inositol + IP6 holds great promise in our strategies for both prevention and therapy of cancer. Inositol + IP6 enhances the anticancer effect of conventional chemotherapy, controls cancer metastases, and improves the quality of life, as shown in pilot clinical studies. Emerging clinical and rather vast amount of laboratory data accumulated so far strongly suggest its role either as an adjuvant or as an "alternative" to current chemotherapy for cancer. In addition to cancer, Inositol + IP6 has great potential in prevention of kidney stones, diabetic complications and atherosclerotic cardiovascular diseases, ailments that afflict people throughout the world.

Therapeutic induction of apoptosis is an important goal of anti-cancer drug design. Here, we review briefly the emerging role of cellular carbonyl stress in melanoma proliferative control, antiapoptotic survival signaling, progression, and metastasis. Cellular carbonyl stress mediated by endogenous reactive carbonyl species (RCS) such as glyoxal, methylglyoxal (MG), and malondialdehyde has been implicated in proliferative signaling and metastasis of human tumor cells. RCS-derived protein-epitopes called advanced glycation endproducts (AGEs) formed from chemical reaction between RCS and tissue proteins are abundant in melanoma tissue, and AGEs are potent ligands of RAGE, a membrane receptor involved in melanoma proliferation and metastasis. In addition to the established role of AGE-RAGE signaling in many human malignancies, increasing experimental evidence supports the hypothesis that RCS, originating from increased tumor cell glycolysis and mitochondrial oxidative stress, are small molecular anti-apoptotic effectors targeting the mitochondrial permeability transition pore (MPTP). We also discuss the emerging role of RCS as novel molecular targets for chemotherapeutic intervention, and provide preliminary experimental evidence that carbonyl scavengers, specific molecular antagonists of RCS, may represent a novel class of anti-melanoma therapeutics.

Aberrant Hedgehog (Hh) signaling plays an important role in the pathogenesis and maintenance of many cancers. The mechanisms by which this pathway contributes to tumor progression are only now being unraveled. There appear to be two distinct ways by which Hh signaling becomes constitutively activated in tumors: by over expression of the ligand itself, or by acquisition of mutations in Hh signaling components at or downstream of the Hh receptor. The goal of this review is to briefly present the key components of the Hh pathway, and then discuss the known inhibitors of this pathway. We will describe how each inhibitor was identified, what is known of its mechanism of action, and its potential as a therapeutic agent against tumors dependent on Hh signaling.

The search for the cause of cancer has led to five successive theories involving viruses, oncogenes, tumor suppressor genes, somatic mutation cascade and inflammation. The latter, without discarding the former theories, is now the prevailing paradigm recognizing that neoplastic cells require participation of the microenvironment for tumor progression. Inflammatory reactions are dependent on an overabundance of immune responses which are both in favor and against tumor development. This homeostatic immunological behavior has led to the concept of tumor immunoediting in an attempt to elucidate why tumors grow. This review is a non-exhaustive description of the different experimental highlights which have led to our present knowledge of cancer. During its 47 years of existence, our laboratory has contributed extensively to the experimental development of onco-immunology, so that our results are described within the background of international discoveries. As for cancer therapy, the many attempts made, both at the experimental and clinical levels, have been mainly frustrating and yet, as oncologists, we are always ready to try again.