Integrating dosimetric and clinical insights: correlating acute bone marrow toxicity with irradiated marrow volume in rectal cancer patients undergoing concurrent chemoradiation

Background: Concurrent chemoradiation is one of the major treatments for locally advanced rectal cancer. As radiation therapy suppresses the bone marrow, it is essential to quantify the dose received by the pelvic bone marrow (PBM), which constitutes about 50% of the hematopoietic bone marrow. Methods: A prospective study conducted in 50 patients with locally advanced rectal cancer treated with long course concurrent chemoradiation. All the patients were followed up with weekly complete blood count for assessing hematological toxicities and were graded. PBM was contoured and subdivided into ilium bone marrow (IBM), lower pelvis bone marrow (LPBM) and lumbosacral bone marrow (LSBM). Volumes of bone marrow receiving different doses were quantified. Results: Among the 50 patients, 40 (80%) developed acute bone marrow toxicity, during the course of treatment. Highest grade of bone marrow toxicity developed in 20 (40%) patients which was grade 2. Compared to grade 1, grade 2 neutropenia patients exhibited significantly higher levels of V10 to V40 (p<0.05) in PBM and significantly higher levels of V20 in IBM and LSBM. In LPBM, compared to grade 1 leukopenia and neutropenia, grade 2 leukopenia and neutropenia exhibited significantly higher levels of V10 and V20 (p<0.05). Conclusions: Increased PBM V10 to V40, IBM V20, LSBM V20, LPBM V10 and V20 were significantly related to the higher grades of neutropenia in locally advanced rectal cancer patients undergoing long course concurrent chemoradiation. Increased LPBM V10 and V20 were also significantly related with higher grades of leukopenia.

Radioprotection by tempol: studies on tissue antioxidant levels, hematopoietic and gastrointestinal systems, in mice whole body exposed to sub- lethal doses of gamma radiation

Ionizing radiation induces the production of reactive oxygen species [ROS], which play an important causative role in cell death. Wholebody exposure of mice to gamma radiation leads to diminution of tissue antioxidant defense systems; increases the peroxidative damage to membrane lipids and damages the haematopoietic and gastrointestinal systems. Tempol [TPL], a cell membranepermeable amphilite nitroxide, shown to protect against cell injury caused by ROS was studied for its radioprotective effects. Animals were administered with TPL at doses of 100 or 200 mg/kg body weight p.o 10 minutes prior to sub- lethal doses [4 or 6 Gy] of whole body gamma radiation exposure. Tempol prevented the radiation induced depletion in RBC and total WBC counts, glutathione content in blood and bone marrow cellularity. TPL also protected the tissue antioxidant system and membrane lipids from the radiation-induced damages. An enhanced spleen colony formation and spleen weight recovery were also observed in radiation exposed mice administered with TPL. The compound also protected the epithelial cells of the gastrointestinal tract from the radiation-induced structural alterations. These preclinical data indicate that TPL may have its potential as a radioprotector during radiation exposure scenarios

A phase I trial of tocoferol monoglucoside in patients undergoing hemi-body radiation.

PURPOSE: To evaluate Tocoferol monoglucoside (TMG), a water soluble vit. E. in a phase I trial, as a radiation protector in those undergoing hemi-body radiation for disseminated disease. MATERIALS AND METHODS: Patients scheduled to receive modified hemi-body radiation were accrued for the study. Patients not only had disseminated skeletal disease but, were heavily pretreated Seven patients were accrued for the study. Patients received 1 and 2 gms of TMG. 30-40 minutes before hemibody radiation. A dose of 600 cGy was delivered on telecobalt equipment at mid plane. Immediate Toxicities were evaluated as well as response to pain. RESULTS: All the seven patients underwent radiation uneventfully. There was no drug related toxicity. Pain relief was adequate. CONCLUSION: Tocoferol monoglucoside an effective antioxidant with no significant acute toxicity, when administered in a dose of 1 or 2 gms per oral route. TMG being water-soluble can have global antioxidant and radio protective effects. This needs further clinical evaluation.

Genetic alterations in cervical cancer.

In the pathogenesis of cervical cancer the role of human papillomavirus (HPV) infection is well established. However, other than HPV infection the genetics of cervical cancer remains poorly understood. In the pathogenesis of cervical cancel three major factors are involved, two of which are related to the presence of HPV and the third is the recurrent genetic alterations not linked to HPV infection. Several chromosomal regions with recurrent loss of heterozygosity (LOH) in cervical cancer have been identified. However; the putative tumor suppressor genes located in these chromosomal locations are yet to be identified. Recurrent amplifications have been mapped to the short arm of chromosome 3 in invasive cancer. Microsatellite instability and mutator phenotype do not play a major role in cervical carcinogenesis. As in other cancers, cervical cancer too requires the accumulation of genetic alterations for carcinogenesis to occur. Identification of these alterations could help to provide a better understanding of the disease and thus improve treatment.

Mitochondrial genome organization and cytoplasmic male sterility in plants.

Plant mitochondrial genomes are much larger and more complex than those of other eukaryotic organisms. They contain a very active recombination system and have a multipartite genome organization with a master circle resolving into two or more subgenomic circles by recombination through repeated sequences. Their protein coding capacity is very low and is comparable to that of animal and fungal systems. Several subunits of mitochondrial functional complexes, a complete set of tRNAs and 26S, 18S and 5S rRNAs are coded by the plant mitochondrial genome. The protein coding genes contain group II introns. The organelle genome contains stretches of DNA sequences homologous to chloroplast DNA. It also contains actively transcribed DNA sequences having open reading frames. Plasmid like DNA molecules are found in mitochondria of some plants Cytoplasmic male sterility in plants, characterized by failure to produce functional pollen grains, is a maternally inherited trait. This phenomenon has been found in many species of plants and is conveniently used for hybrid plant production. The genetic determinants for cytoplasmic male sterility reside in the mitochondrial genome. Some species of plants exhibit more than one type of cytoplasmic male sterility. Several nuclear genes are known to control expression of cytoplasmic male sterility. Different cytoplasmic male sterility types are distinguished by their specific nuclear genes (rfs) which restore pollen fertility. Cytoplasmic male sterility types are also characterized by mitochondrial DNA restriction fragment length polymorphism patterns, variations in mitochondrial RNAs, differences in protein synthetic profiles, differences in sensitivity to fungal toxins and insecticides, presence of plasmid DNAs or RNAs and also presence of certain unique sequences in the genome. Recently nuclear male sterility systems based on (i) over expression of agrobacterial rol C gene and (ii) anther specific expression of an RNase gene have been developed in tobacco and Brassica by genetic engineering methods.

Dipyrone-induced changes in DNA repair and other cell membrane associated processes in Escherichia coli.

The analgesic, dipyrone (l,phenyl 2,3 dimethyl 5 pyrazolone 4 methyl amino methane sulphonate sodium), at 20 mM concentration, inhibited the rejoining of single strand scissions in DNA of Escherichia coli B/r cells induced by 20 krad gamma radiation. The chemical altered the cell membrane structure as evidenced from the uptake of acriflavin, the efflux of potassium ions from the bacterial cells and the inhibition of alkaline phosphatase a cell membrane associated enzyme.