Current Cancer Therapy Reviews - Volume 1, Issue 2, 2005

Objective: To review recent epidemiologic studies of vaccination and melanoma risk as well as critically discuss the different melanoma vaccines under investigation in multicenter phase III melanoma vaccine trials. Data Sources: A retrospective review of the literature. Study Selection: Studies included those on the risk of melanoma and vaccination, historically relevant data, and ongoing or recently published phase III melanoma vaccine trials. The referenced study designs and methodologies varied. Data extraction and Synthesis: 3 reviewers extracted Data and the main results are presented in a quantitative descriptive manner. Conclusion: Vaccine therapy of melanoma remains promising, given the associated low toxicity. Epidemiologic studies suggest a role for vaccines against certain infectious diseases in melanoma prevention. While results of ongoing phase III melanoma vaccines trials may open new avenues for disease prevention, a better understanding of immune responses to melanoma vaccines will be necessary.

The strategy in the treatment of metastatic renal cell carcinoma (MRCC) is based on prognostic factors for survival. General performance status, delay from the diagnosis of primary tumor to occurrence of metastases, number of metastatic sites or site of metastases (lung, liver) and biological changes such as hemoglobin value, calcium value, and sedimentation rate are reported as the most predictive factors for survival. The first line of treatment in MRCC is immunotherapy for the majority of patients. Disagreement remains regarding the choice of immunotherapy: interleukin-2 (IL-2) and/or interferon alpha; and the mode of administration of IL-2: intravenous or subcutaneous route. Major therapeutic changes are coming with new drugs directed against new targets. Bevacizumab, an anti-Vascular Endothelial Growth Factor (VEGF) has been approved in second-line treatment. Other compounds are under investigation such as drugs targeting the EGF and Ras pathways.

Methylation of CpG islands in many tumor suppressor genes with or without changes in histone acetylation is an important mechanism of gene silencing during the development of different types of cancer. There are at least two types of CpG island methylator phenotypes in intestinal- and diffuse -types of gastric cancer. Hypermethylation of the p16 and of hMLH1 promoters is preferentially found in intestinal-type gastric carcinoma, while concordant hypermethylation of the CDH1 and RAR-β2 promoters is predominantly associated with diffuse-type gastric carcinoma. Loss of RUNX3 and pS2 expression by promoter methylation is a common event in both types of gastric carcinoma. These results suggest that CpG island methylator phenotype may be one of the major pathways responsible for the development of the two types of gastric cancer and that RUNX3 and RAR-β2 may provide potential targets for therapeutic intervention to treat gastric cancer. Reactivation of RUNX3 and RAR-β2 by demethylating agents [e.g., 5-aza-2-deoxycytidine (DAC)] and histone deacetylase (HDAC) inhibitors [e.g., suberoylanilide hydroxamic acid (SAHA)] may be clinical useful for gastric cancer therapy with retinoids. This article will provide an overview of the molecular machinery that underlies two types of gastric cancer and focus on HDAC inhibitors that are potentially effective anticancer agents, not only for breast and prostate cancers but also for gastric cancer.

Cancer of the digestive tract is a major cause of cancer-associated morbidity and mortality worldwide. Secondary prevention and treatment of early lesions is extremely important because the etiology of gastrointestinal cancer remains largely unknown. Precursor lesions can be identified with imaging techniques and histology. The macroscopic pattern seen during endoscopy includes polyps and non-polypoid lesions. The microscopic epithelial alterations of the precursor lesions include cytological and architectural abnormalities formerly called “dysplasia”. Recently, “dysplasia” has been replaced by “intraepithelial neoplasia”. Although intraepithelial or non-invasive neoplasia forms a spectrum, reflecting underlying genetic abnormalities, the lesion is usually graded according to the degree of severity. Follow up and treatment strategies are planned accordingly. It has been recognised also that “hyperplastic polyps”, which do not necessarily show the features of intraepithelial neoplasia are in fact a heterogeneous group and some of these have neoplastic potential. The definition of malignancy and the microscopic features used for the identification of cancer are not universally uniform. Therefore, comparison of articles from different continents is not always possible. In order to avoid confusion, new terminologies and definitions have been proposed and are currently introduced. The purpose of this minireview is to describe the most recent terminologies and definitions, which can be correlated with treatment strategies.

Thyroid carcinoma arising from normal follicular cells is generally slow-growing with an excellent prognosis if competently resected. However, once the tumor dedifferentiates and becomes undifferentiated (anaplastic) carcinoma, it becomes one of the most aggressive malignancies. Such a polarized characteristic is quite unique yet typical of thyroid carcinoma. To date, many researchers have studied differences in the characteristics of thyroid carcinoma before and after dedifferentiation. In this review, the difference in cell proliferating activity and the expression of cell cycle modulators is addressed. Cell proliferating activity of undifferentiated carcinoma is definitely higher than that of differentiated carcinoma. However, expression of cell cycle modulators in thyroid carcinoma is often unique and even discrepant. Some negative modulators are diffusely expressed and reduced expression of some positive modulators can be observed in undifferentiated carcinoma. We described these interesting findings in thyroid carcinoma in this review.

Background: Squamous cell carcinoma metastatic to the neck from an unknown head and neck primary site is relatively uncommon and presents a challenging diagnostic and therapeutic dilemma. Methods: Review of the pertinent literature. Results: Diagnostic evaluation includes fine needle aspirate of the neck mass, chest roentgenography, computed tomography, and/or magnetic resonance imaging of the head and neck, followed by panendoscopy and directed biopsies. Ipsilateral tonsillectomy is indicated unless there is no lymphoid tissue in the tonsillar fossa. The primary tumor will be detected in approximately 40% of patients; about 80% of cancers are located in the base of tongue or tonsillar fossa. Optimal treatment is controversial. Options include treatment of the neck alone or both sides of the neck and the potential head and neck primary sites. The latter approach is associated with better local-regional control. Therefore, patients with N1 disease without extracapsular extension may be treated with a neck dissection alone and followed closely as long as an open biopsy was not performed prior to surgery. Few patients meet these criteria. Those with more advanced disease and/or a violated neck receive radiotherapy (RT) to the oropharynx, nasopharynx, and both sides of the neck, followed by evaluation for a neck dissection. Patients with advanced N2 or N3 disease receive adjuvant chemotherapy concomitantly with RT. The 5-year survival rate is approximately 50% and is influenced by the extent of neck disease. Conclusions: Diagnostic evaluation identifies the primary site in about 40% of patients; the majority are in the tonsillar fossa or tongue base. Treatment depends on extent of disease and yields a 5-year survival rate of about 50%.

Prostate cancer (PCa) is the most frequently diagnosed cancer and the second leading cause of cancer death in western men, and as such constitutes a significant health problem. The male sex steroids, androgens, have long been recognized as major contributors to the progression of PCa. Still today, standard therapy for PCa is aimed at removing androgens and/or blocking the action of androgens. Although most PCas initially regress following anti-androgen therapy, a majority of these tumors eventually start to regrow, leaving the patient very little hope of curative treatment. Interestingly, in androgen-refractory PCas the androgen receptor (AR), the transcription factor mediating the effects of androgens, continues to be expressed, and AR signaling remains functional. Moreover, disruption of the activity or the expression of the AR inhibits proliferation of androgen-refractory PCa cells, emphasizing that, in the androgen-independent state of the disease, ARmediated signaling is crucial to the survival of PCa cells. Several potential mechanisms, most likely not mutually exclusive, have been described to account for activation of the AR in androgen-refractory PCa cells. Recent reports of aberrant expression of coregulators that are required for the formation of productive AR transcriptional complexes in androgen-refractory PCa and its correlation with PCa disease progression, have enhanced interest into this mechanism and have led to the proposition of AR coregulator protein complexes as potential novel targets for PCa therapy. This review seeks to critically analyze the current knowledge on AR coregulator expression in PCa tissues and to evaluate how this information could translate into novel therapeutic targets for PCa.

Autocrine motility factor (AMF) is a type of tumor-secreted cytokine stimulating cell motility via AMF receptor (AMFR)-mediated signaling pathways. There are many reports that enhanced AMF levels and AMFR overexpressions are correlated with the tumor progression and its malignancy. It is thought previously that AMF is a tumor-specific factor functioning in an autocrine manner, however, recent studies show that tumor-secreted AMF stimulates normal cell motility in a paracrine manner, and promotes angiogenesis and other pathological phenomena. AMF is also involved with vascular endothelial growth factor (VEGF), which is the most important tumor angiogenic and mitogenic factor. Hypoxia-induced AMF is regulated by VEGF, furthermore, the signaling of AMF-AMFR in host endothelial cells induces expression of a VEGF receptor Flt- 1. This malignant cycle comprising of Flt-1, VEGF and AMFR will result in marked locomotive, angiogenic and further metastatic synergy. Experimental treatment with AMF inhibitors succeeded in reducing tumorinduced angiogenesis and accumulation of ascites fluid, which renders AMF to the target molecule. It is further suggested that AMF brings anti-apoptotic ability to the tumor cell itself to gain a resistance against anticancer drugs. AMF inhibitors could support the anti-cancer drugs due to its ability to lead the tumor cells to cell death. This article reports that AMF is a significant factor associated with the development of tumors, and it will be a new target for anti-cancer treatment.

There are many biological plausible reasons, which showed that plant food could prevent/delay the appearance of many diseases including cancer. Garlic has been reported to possess therapeutic properties from centuries and is probably the most widely studied medicinal plant. Garlic contains a number of organosulfur compounds such as SAC, S-allyl mercaptocysteine, allicin, ajoene, DAS and other structurally related compounds, which are widely believed to be active agents in preventing cancer. Epidemiological as well as experimental studies have provided sufficient evidences that garlic along with its organosulfur components possess pleiotropic beneficial health effects including antioxidative, antimutagenic and anti-tumorigenic properties.