Narrow Results

Nuclear microprobe analysis studies in cancer cell pharmacology and biology carried out at Bordeaux-Gradignan are reported. The cellular pharmacology of two anticancer agents, cis-diammine-dichloroplatinum(II), and 4′-iodo-4′-deoxy-doxorubicin, were investigated, as well as the role of iron in neuroblastoma carcinogenesis, and chromium(III) in trans-generation carcinogenesis. Nuclear microprobe analysis, using PIXE and particle backscattering microanalysis, was able to reveal intracellular and tissue distributions of the elements under investigation. Moreover, the fully quantitative and multi-elemental character of nuclear microprobe analysis offered information on possible mechanisms of drug action, metal carcinogenesis, and interactions with endogenous trace elements in cancer cells.

Inflammatory bowel disease increases the risks of human colorectal cancer. In this study, the effects of Salvia miltiorrhiza extract (SME) on chemically-induced colitis in a mouse model were evaluated. Chemical composition of SME was determined by HPLC analysis. A/J mice received a single injection of AOM 7.5 mg/kg. After one week, these mice received 2.5% DSS for eight days, or DSS plus SME (25 or 50 mg/kg). DSS-induced colitis was scored with the disease activity index (DAI). Body weight and colon length were also measured. The severity of inflammatory lesions was further evaluated by colon tissue histological assessment. HPLC assay showed that the major constituents in the tested SME were danshensu, protocatechuic aldehyde, salvianolic acid D, and salvianolic acid B. In the model group, the DAI score reached its highest level on Day 8, while the SME group on both doses showed a significantly reduced DAI score (both p < 0.01). As an objective index of the severity of inflammation, colon length was significantly shorter in the model group than the vehicle group. Treatment with 25 and 50 mg/kg of SME inhibited the shortening of colon in a dose-related manner (p < 0.05 and p < 0.01, respectively). SME groups also significantly reduced weight reduction (p < 0.05). Colitis histological data supported the pharmacological observations. Thus, Salvia miltiorrhiza could be a promising candidate in preventing and treating colitis and in reducing the risks of inflammation-associated colorectal cancer.

ASIA – New findings reveal a key cause of failed pregnancies and birth defects.

ASIA – Uncontrolled hypertension in rural communities.

ASIA – HKBU develops world-first metal-based probes for detection of dopamine receptors, a cancer biomarker.

ASIA – Activation switch for cancer metastasis discovered.

ASIA – NUS researchers uncover novel pathway in development of acute myeloid leukemia with poor prognosis.

ASIA – Southern Campus of Academia Sinica officially breaks ground.

ASIA – Singapore team finds new molecule that can grow blood stem cells for transplant.

ASIA – Faster genome evolution methods to transform yeast for industrial biotechnology.

ASIA – Cometh the cyborg: improved integration of living muscles into robots.

ASIA – Pigs that digest their nutrients could reduce pork industry’s carbon footprint.

We present two different mathematical models that examine the role of cellular evolution in the development and treatment of cancer. The first is a Lotka-Volterra model of an invasive cancer subjected to chemotherapy that demonstrates rapid evolution of drug-resistant phenotypes. The second model represents a major refinement of the first one with the objective of producing a simple, but realistic model of carcinogenesis. It is a consumer-resource model (consumers = normal + mutuant cells, resource = glucose). We conclude that if mutant cells are not allowed to evolve, they will not ordinarily progress to cancer. However, if accumulating mutations allow cellular evolution and successful adaptation to proliferation constraints, normal cells will develop into invasive cancer. We find this progression is possible because normal cellular populations are not at an evolutionarily stable state and so are subject to invasion by more fit phenotypes.

This paper presents result of QSTR (quantitative structure–toxicity relationship) study obtained using the PRECLAV software. The dependent property is toxicity against rat (Rattus norvegicus), measured by TD₅₀ values. The calibration/training/learning set includes 49 molecules having a very high chemical diversity. There are five outliers in calibration set. In the presence of outliers the predictive power of QSTR is very low (r² = 0.5425, F = 10.4, ). After elimination of outliers the predictive power of QSTR is much higher (r² = 0.9078, F = 44.3, ). All eight predictors are nonlinear functions (parabolic and products) of descriptors. The LogP is not predictor. Presence of C = CH₂ and N–NO molecular fragments increases toxicity. Presence of C₆H₄ molecular fragment decreases toxicity.

Diethylstilbestrol (DES) is a synthetic nonsteroidal estrogen that was used by millions of pregnant women in the United States to prevent miscarriages and other pregnancy-related complications between 1938 and 1971. In 1971, the U. S. Food and Drug Administration issued a warning against the use of DES during pregnancy after a relationship was found between exposure to DES during the first trimester of pregnancy and the development of clear cell adenocarcinoma of the vagina and cervix in young women whose mothers had taken DES during pregnancy. Additional side effects associated with DES included an increased risk for breast cancer in women who took DES during pregnancy and structural reproductive tract anomalies, increased infertility, and poor pregnancy outcomes for women who were exposed to DES in utero. Compilation of the various sites of DES toxicity in humans and experimental animals indicates that lesions appear predominantly in estrogen-responsive target tissues suggesting that the presence of the estrogen receptor (ER) in such target tissues may help to govern the toxic effects of DES. Interestingly, it should be noted that DES, despite its adverse effects in reproductive endocrinology, was the fi rst successful “chemical therapy” for cancer. Specifi cally, DES was available for the treatment of advanced prostate and breast cancer from the 1940s up until the 1990s. This review discusses the long-term health implications of DES for mothers, DES daughters and DES sons, and the possible side effects of DES on the third generation. We also propose possible mechanism(s) of actions of DES as a carcinogen and its paradoxical action as the first effective hormonal therapy for prostate and breast cancer.

Cancer Stem Cells (CSCs) are a small population of cells within tumors holding stemness properties that sustain cancer progression, such as enhanced capacities for self-renewal, growing, metastasizing, homing, and reproliferating. CSCs show remarkable organizing capacities as they can educate neighboring cells to provide nutrients and collaborate in the elusion from the immune system, creating an environment favorable for tumor growth. In particular, tumor-specific microenvironments comprise stromal cells, immune cells, networks of cytokines and growth factors, hypoxic regions, and the extracellular matrix. The contribution of the microenvironment in this picture is crucial: it is now accepted that the “cancer” scenario is not simply composed of transformed cells working together in isolated and strictly autonomous machinery. Tumor microenvironment actively collaborates with neoplastic cells at different levels: promoting proliferation while evading growth suppression and immune surveillance, overcoming cell death, modulating cell metabolism, activating angiogenesis and invasion/metastasis programs. Also, the interactions between CSC and microenvironment help in their survival of common anti-cancer therapies thus being partly responsible for disease recurrence. Further studies regarding CSC/microenvironment seem to be promising for new CSC-targeting therapies, which may represent an innovative strategy for the cure of lung cancer.

Loss of heterozygosity (LOH) of the chromosomal region 11q22-q24 is common in several types of human solid neoplasms, including carcinomas of the breast, lung, colon, nasopharynx, cervix, ovary, uterus and malignant melanoma, suggesting the presence of one or several tumour suppressor genes in this region. To determine if LOH occurs in this chromosomal region in tumours of the central nervous system, we screened for LOH in matched normal and tumour DNA samples from 32 patients with primary tumours of the CNS, of which 20 were benign and 12 were malignant. Nine polymorphic microsatellite loci from the 11q22-q23 region, between D11S940 and D11S934 were analyzed by the polymerase chain reaction (PCR). Six of the 32 cases (18.8%) demonstrated LOH at one or more of the nine loci studied and no significant increase in the frequency of LOH was observed at any particular locus. Of these six cases with LOH, two were benign and four were malignant tumours. Since LOH was detected in both benign and malignant cases, we conclude that LOH at the chromosomal region 11q22-q23 in tumors of the CNS is a random event and may not play an important role in the pathogenesis of these tumours.

There have been some results reported concerning the expression of metallothionein (MT) in colorectal tumors. This paper reviews four aspects: the contribution of MT in colorectal carcinogenesis, the prognostic significance of MT, MT expression in colorectal liver metastases, and the clinical significance of MT as a drug-resistance protein.

Although cancer has been considered a disease of deoxyribonucleic acid (DNA), the fundamental dogma that cancer is the result of cumulative mutations that alter specific locations in a cell's DNA is facing challenges. Several major hypotheses of carcinogenesis associated with epi-genetic factors are reviewed. Warburg proposed that cancer is caused by irreversible damage to the aerobic respiration capacity of normal cells; Pauling suggested that a deficiency of vitamin C was a cause of carcinogenesis; and Szent-Györgyi proposed a bioelectrical conductivity hypothesis. Deficiency of micronutrients such as folic acid, vitamin B₆, B₁₂, choline, methionine, iron, and zinc are factors that cause cancer. A decrease of cellular nicotinamide adenine dinucleotides concentration and niacin deficiency are also suggested to be involved in the evolution of cancer formation. Dysfunctional gap junctional intercellular communication (GJIC) caused by environmental carcinogens was proposed to be a cause of cancer. The alterations in DNA methylation is also considered to be a cause of carcinogenesis. Chromosomal abnormalities and viral infections also cause cancers. Each hypothesis, which has survived long scrutiny and many trials, led to a valuable study of a particular facet in the complicated processes related to both normal and cancerous cells. It is important to study how these various hypotheses are interrelated and attempt to integrate all different facets of cancer cells into a plausible mechanism of carcinogenesis. It would also be beneficial for future research efforts to study the synergistic effects of both epigenetic factors and genetic alterations on normal cells.

Genetically modified mouse models serve as useful in vivo tools to confirm or refute the involvement of specific drug-metabolizing enzymes, including the arylamine N-acetyltransferases (NATs), in drug or xenobiotic metabolism, toxicity and carcinogenesis. Several NAT mouse models have been generated, including congenic lines of naturally polymorphic rapid and slow acetylator strains, targeted knockout mouse models and ‘humanised’ transgenic mice, to interrogate the involvement of NAT enzymes in these processes and during normal physiology and development. While no overt phenotypes have been observed in NAT-knockout mouse strains, several lines of evidence arising from studies conducted using murine and human NAT1/2 transgenic mice have alluded to the existence of potential endogenous roles that are distinct from ‘classical’ metabolism of foreign compounds, and may involve the integration or intersection of different cellular metabolic pathways that affect general health and disease.

We use a range of mathematical modelling techniques to explore the acid-mediated tumour invasion hypothesis. The models make a number of predictions which are experimentally verified. The therapeutic implications, namely either buffering acid or manipulating the phenotypic selection process, are described.