Mitochondria and tumors: a new perspective.

BACKGROUND: Mitochondrial DNA (Mt DNA) defects have been identified in a variety of Tumors, but the exact role of these defects in the pathogenicity and tumor progression is poorly understood. This study aims at identifying the status of mitochondrial OXPHOS genes in neoplastic transformation and attempts to establish a cause and effect relationship between mitochondrial OXPHOS defects and tumor progression. MATERIALS AND METHODS: Mutational, expression and functional analysis of l2 of the 13 mitochondrial OXPHOS genes has been carried out using PCR, Real-Time PCR and protein modeling in 180 sporadic samples of a heterogeneous group of benign and malignant tumors like that of benign, malignant, matched blood and adjacent normal tissue of breast and benign hemangioma. RESULTS: Mutations were identified in the ND4L, ND6 and COX-II regions of the mitochondrial OXPHOS genes. All the mutations were limited only to the malignant breast tissues. On relative quantification, a compromised expression of OXPHOS genes was identified in all the malignant tissues irrespective of their mutational states. Protein modeling revealed loss of function mutations of ND6 and COX-II proteins. CONCLUSION: This is the first study worldwide wherein a comparative study using different benign and malignant tumors has been carried out to assess the role of Mt DNA defects. Our data reveals mitochondrial dysfunction only in malignant cells and not in their benign counterparts, indicating that the dysfunction may arise after the pro-proliferative pathway has set in. We hypothesize that compromised OXPHOS may be a responsive mechanism of the cell to counter cancers, rather than a mechanism of initiating tumorigenesis.

Effect of polyunsaturated fatty acids on diphenyl hydantoin-induced genetic damage in vitro and in vivo.

Phenytoin sodium/diphenyl hydantoin (DPH) is used by a major segment of epileptics and neuro surgery patients with head injury to prevent seizures. DPH is a known mutagen, carcinogen, and teratogen. Essential fatty acids (EFAs) are critical for various tissues and were reported to act as anti-mutagenic agents. In the present study we assessed the effect of five EFAs on DPH-induced genetic damage both in vitro and in vivo. DPH induced significant genetic damage. Of all the EFAs (linoleic acid, alpha-linolenic acid, gamma-linolenic acid, arachidonic acid, dihomo-gamma-linolenic acid, and eicosapentaenoic acid) studied, all except eicosapentaenoic acid showed significant decrease in DPH induced genetic damage as assessed by micronucleus (MN) test. However, gamma-linolenic acid (GLA) was found to be the most effective in reducing the number of MN containing lymphocytes both in vitro and in vivo to control values. EFAs when tested alone produced insignificant increase in the amount of genetic damage but when tested in combination with DPH the number of micronuclei containing lymphocytes was reduced; but the DNA ladder pattern, an indication of DNA damage, was increased. This apparently paradoxical action of EFAs, especially of GLA, suggests that, in all probability, fatty acids induce apoptosis of cells that harbor significant DNA damage. Based on these results we suggest that GLA functions as a unique endogenous molecule that protects cells from accumulating genetic damage.

Effect of gamma-linolenic acid and prostaglandins E1 on gamma-radiation and chemical-induced genetic damage to the bone marrow cells of mice.

The effect of gamma-linolenic acid (GLA) and prostaglandin E1 (PGE1) on gamma-radiation, diphenylhydantoin (DPH), benzo(a)pyrene (BP), and 4-alpha-phorbol-induced genetic damage to the bone marrow cells of mice, using the sensitive micronucleus (MN) test was investigated. PGE1 and its precursor GLA prevented gamma-radiation, DPH, BP, and 4-alpha-phorbol-induced genetic damage.

Thermoluminescence measurements of gamma-ray doses attributable to fallout from the Nevada test site using building bricks as natural dosimeters.

During the 1950's, the U.S. Government conducted an intensive atmospheric nuclear testing program in Nevada. Fallout from these atmospheric tests was measured throughout the U.S. with some of the heaviest concentrations to populated areas falling east of the test site in Washington County, UT. External exposures from 6.5 x 10(-4) C kg-1 to 26 x 10(-4) C kg-1 (2.5-5.0 R) were reported for this region. This study provides an independent measurement of fallout radiation doses to selected communities in Utah using a thermoluminescence technique originally developed for the dating of ancient pottery. The application of the predose thermoluminescence technique to fallout dosimetry is described. A mean dose of 38 +/- 15 mGy (4.4 +/- 1.7 R), attributed to fallout radiation, was measured in quartz grains extracted from the outer centimeter of bricks removed from six communities in Washington and Kane Counties in Utah.