Mohan C. Pant

Evidence for increased cytochrome P450 1A1 expression in blood lymphocytes of lung cancer patients

To develop blood lymphocyte cytochrome P450 1A1 (CYP1A1) expression as a surrogate for monitoring tissue expression for polycyclic aromatic hydrocarbon (PAH) induced toxicity, the present study attempted to characterize CYP1A1 mRNA expression and its associated catalytic activity in freshly prepared blood lymphocytes isolated from healthy controls and patients suffering from tobacco induced lung cancer. Human blood lymphocytes were found to express CYP1A1 mRNA and significant activity of 7-ethoxyresorufin-O-deethylase (EROD). Significant increase in the activity of EROD and CYP1A1 mRNA was observed in blood lymphocytes isolated from patients suffering from lung cancer. Further, controls with variant genotypes of CYP1A1 (Msp1 or Ile/Val polymorphism) exhibited significant increase in the enzyme activity associated with an increase in CYP1A1 mRNA expression when compared to the controls with wild type genotype. Patients with variant genotypes of CYP1A1 also exhibited much greater increase in the blood lymphocyte CYP1A1 mRNA expression and EROD activity when compared to controls or patients with wild type genotype. Our data thus provides evidence of CYP1A1 expression in freshly isolated blood lymphocytes and differences in reactivity in individuals with variant genotypes of CYP1A1, suggesting that blood lymphocyte CYP1A1 expression profile could help in identifying individuals at risk to environment induced lung cancer.

Cytochrome P450 2E1 and head and neck cancer: interaction with genetic and environmental risk factors.

The present case‐control study investigates the association of polymorphisms in cytochrome P450 2E1 (CYP2E1), involved in the metabolism of tobacco carcinogens and alcohol, with Head and Neck Squamous Cell Carcinoma (HNSCC). In addition, the interaction of CYP2E1 (CYP2E1*5B and CYP2E1*6) with other genetic factors (null genotype of glutathione‐S‐Transferase M1, GSTM1, X‐Ray Repair Cross Complementing Group I, XRCC1 (Arg194Trp), and environmental risk factors such as alcohol and tobacco in modifying HNSCC risk were investigated. Genotypes were determined by the polymerase chain reaction‐restriction fragment length polymorphism (PCR‐RFLP) assay in a total of 350 male cases of HNSCC and an equal number of healthy male controls. Statistical analysis showed a significant increase in HNSCC risk in cases with variant genotypes of CYP2E1*5B (RsaI) (O.R. 3.44; 95% C.I. 1.45–8.14) and CYP2E1*6 (DraI) (O.R. 1.76; 95% C.I. 1.28–2.41). Haplotype analysis revealed that haplotype T‐A was associated with a greater than 10‐fold increase in risk for HNSCC. Our data also revealed a several fold increase in HNSCC risk in cases carrying a combination of variant genotypes of CYP2E1 with the null genotype of GSTM1 or XRCC1 variant genotypes. Alcohol or tobacco use (both smoking and chewing) were also found to interact with variant genotypes of CYP2E1 in significantly enhancing HNSCC risk. This increase in risk associated with an interaction of CYP2E1 genotypes with GSTM1 or XRCC1 or with tobacco and alcohol use demonstrates the importance of gene–gene and gene–environment interactions in the development of HNSCC. Environ. Mol. Mutagen. 2009.

Associated risk of XRCC1 and XPD cross talk and life style factors in progression of head and neck cancer in north Indian population.

Effective DNA repair machinery ensures maintenance of genomic integrity. Environmental insults, ageing and replication errors necessitate the need for proper DNA repair systems. Any alteration in DNA repair efficacy would play a dominant role in progression of squamous cell carcinoma of head and neck (SCCHN). Genotypes of XRCC1 gene-Arg194Trp, Arg280His, Arg399Gln and XPD Lys751Gln, by PCR-RFLP were studied in 278 SCCHN patients and an equal number of matched healthy controls residing in north India. In XRCC1 polymorphisms, Arg194Trp and Arg399Gln variants showed a reduced risk, whereas, XPD Lys751Gln variants exhibited ∼2-fold increase in SCCHN risk. With XRCC1-Arg280His variants, there was no association with SCCHN risk. Arg399Gln of XRCC1 appears to have a protective role in people those consume alcohol, while XPD Lys751Gln variants indicated ∼2-fold increased risk of SCCHN in all the co-variate groups. Comparison of gene-gene interaction among XRCC1 Arg280His and XPD Lys751Gln suggested enhanced risk of SCCHN by ∼2.3-fold in group one and ∼6.1-fold in group two. In dichotomized groups of this combination, the risk was ∼2.4 times. Haplotype analysis revealed the frequency of C-G-G-G and C-A-G-G to be significantly associated with an increased risk of SCCHN. On the contrary, T-G-A-A significantly diminished the risk. CART analysis results showed that the terminal node that contains homozygous mutants of XPD Lys751Gln and XRCC1 Arg194Trp, wild type of XRCC1 Arg399Gln and homozygous mutant of XRCC1 Arg280His, represent the highest risk group. Our results demonstrate high degree of gene-gene interaction involving DNA repair genes of NER and BER pathways, namely XRCC1 and XPD. This study amply demonstrates positive association of XPD Arg751Gln polymorphism with an increased risk of SCCHN. Further, XRCC1 Arg280His variant though dormant individually, may also contribute to the development of cancer in combination with XPD Arg751Gln.

Association of functionally important polymorphisms in cytochrome P4501B1 with lung cancer.

In the present study, genotype and haplotype frequencies of four polymorphisms of cytochrome P450 1B1 (CYP1B1) that cause amino acid changes (Arg-Gly at codon 48, Ala-Ser at codon 119, Leu-Val at 432 and Asn-Ser at codon 453) were studied in 200 patients suffering from lung cancer and equal number of controls. A significant difference was observed for the distribution of variant genotypes of CYP1B1Arg48Gly and Ala119Ser polymorphisms (CYP1B1*2) in cases when compared to the controls. No significant difference was observed for the distribution of variant genotypes of CYP1B1Leu432Val (CYP1B1*3) and CYP1B1Asn453Ser (CYP1B1*4) polymorphism. When the four SNPs were analyzed using a haplotype approach, SNPs at codon 48 (Arg48Gly) and codon 119 (Ala119Ser) exhibited complete linkage disequilibrium (LD) in all the cases and controls. Significant differences in the distribution of the three haplotypes (G-T-C-A, G-T-G-A and G-T-C-G) were observed in the cases when compared to controls. Tobacco use in the form of smoking as well as chewing was found to significantly increase the risk of lung cancer in patients by interacting with CYP1B1Ala119Ser genotypes demonstrating the role of gene-environment interaction in lung cancer. Further, the risk of lung cancer increased several fold in the patients carrying the genotype combinations of CYP1B1Ala119Ser and CYP1B1Leu432Val with GSTM1, a phase II enzyme suggesting the importance of gene-gene interactions in enhancing the susceptibility to lung cancer.

Circadian variation in radiation-induced intestinal mucositis in patients with cervical carcinoma†

Mucositis, a radiotherapy‐associated toxicity, is an important factor determining morbidity and treatment compliance. Gastrointestinal mucositis in patients undergoing radiotherapy may also depend on time of administration of radiation in addition to several other factors. The presence of any correlation between the severity of acute gastrointestinal mucositis in cervical carcinoma patients and the time of irradiation was prospectively evaluated.

Polymorphism in cytochrome P450 1A2 and their interaction with risk factors in determining risk of squamous cell lung carcinoma in men

The present case-control study was carried out to investigate the association of functionally important polymorphisms of cytochrome P450 1A2 (CYP1A2) involved in the metabolic activation of tobacco derived procarcinogens with squamous cell carcinoma (SCC) of lung in North Indian men. The study consisted of 200 male cases with SCC of lung and an equal number of age and sex matched healthy controls. Our data showed that variant genotype of CYP1A2*1D and CYP1A2*1F were significantly associated with increased susceptibility to SCC of lung. Likewise, GSTM1 null genotype was found to be over represented in patients when compared to controls. Haplotype analysis revealed that haplotype, G-Tdel-T-C was significantly associated with risk to SCC of lung. Moreover, a significant increase in the risk to SCC of lung in the cases carrying combination of variant genotype of CYP1A2 with either CYP1A1 or GSTM1 have shown that gene-gene interactions may play an important role in squamous cell lung cancer risk. Our data also revealed that smokers or tobacco chewers carrying variant alleles of either CYP1A2*1D or CYP1A2*1F were at increased risk to SCC of lung, further demonstrating that CYP1A2 genotypes interact with environmental risk factors in enhancing the risk to squamous cell lung carcinoma.

Polymorphism in cytochrome P450 2A6 and glutathione S-transferase P1 modifies head and neck cancer risk and treatment outcome

A case control study was carried out to investigate the association of functionally important polymorphism in cytochrome P450 2A6 (CYP2A6) and glutathione S-transferase P1 (GSTP1) genes with head and neck squamous cell carcinoma (HNSCC) and treatment response in cases receiving a combination of chemo-radiotherapy. The study group consisted of 350 males suffering from HNSCC and an equal number of male controls. Multivariate logistic regression analysis revealed statistically significant decrease in risk to HNSCC in cases with variant genotypes (CYP2A6*1B and CYP2A6*4C) of CYP2A6 (OR: 0.78; 95% CI: 0.43-1.22; P=0.04) or GSTP1 (OR: 0.71; 95% CI: 0.51-1.00; P=0.05). The risk associated with these variant genotypes was found to be further decreased in cases carrying a combination of variant genotypes of CYP2A6 and GSTP1 (OR: 0.40; 95% CI: 0.25-0.65; P=0.00). A similar decrease in risk was observed in cases with variant genotypes of CYP2A6 (OR: 0.59; 95% CI: 0.40-0.86; P=0.00) or GSTP1 (OR: 0.62; 95% CI: 0.42-0.91; P=0.01) and who were regular tobacco users (cigarette smokers or tobacco chewers). Interestingly, only 27% of the cases carrying the variant forms of CYP2A6 (*1A/*4C+*1B/*4C+*4C/*4C) responded to the treatment for HNSCC when compared to those with wild-type genotype (69%). However with GSTP1, cases with homozygous mutant genotype (Val/Val) showed a superior treatment response (75%) when compared to cases with wild-type genotype (25%). Further, cases carrying a combination of variant genotype of CYP2A6 and wild-type genotype of GSTP1 exhibited a very poor treatment response demonstrating that polymorphisms in CYP2A6 and GSTP1 not only modified the risk to HNSCC but also played a major role in determining the chemotherapeutic response.

Polymorphism in cytochrome P4501A1 is significantly associated with head and neck cancer risk.

A case control study was undertaken to investigate the association of polymorphisms in cytochrome P4501A1 (CYP1A1) with squamous cell carcinoma of head and neck (HNSCC) in North Indian population. The variant genotypes of CYP1A1*2A and CYP1A1*2C were found to be overrepresented in cases when compared to controls. The HNSCC risk also increased several folds in cases with combination of variant genotypes of CYP1A1*2A or CYP1A1*2C with null genotype of glutathione-S-transferase M1 (GSTM1), a phase II enzyme, particularly in cases who were tobacco users (smokers and tobacco chewers), demonstrating the role of gene–gene and gene–environment interactions in the development of HNSCC.

Role of recombinant human erythropoietin in patients of advanced cervical cancer treated "by chemoradiotherapy".

Background: Cervical cancer, in women, is the second most common cancer world wide, next to breast cancer. During the treatment of carcinoma cervix, anemia is selectively frequent and its origin is complex combining hemorrhage, iron deprivation, inflammatory reactions and infection. The objective of this study is to evaluate the role of epoetin in correction of anemia and on treatment outcomes in patients with advanced cervical cancer receiving concurrent chemoradiotherapy. Results: A total of 120 patients were enrolled in the study of which 60 patients were randomized to receive epoetin beta in the treatment arm and 60 patients were in control arm where epoetin beta was not given. Total two and three patients absconded during treatment from treatment and control arm respectively; therefore total evaluable patients were 115. Mean Hb at baseline in the control arm was 10.70 +/- 0.62 g/dl and 10.45 +/- 0.43 g/dl in the treatment arm (p = NS). At the end of treatment mean Hb increased by 1.55 g/dl in patients receiving epoetin beta (p < 0.01), but decreased by 1.50 g/dl in the control arm (p < 0.01). There was significant reduction in blood transfusion in patients receiving epoetin beta (p < 0.01). At the end of treatment there was also significant improvement in energy level, activity level and overall quality of life in the treatment arm (p < 0.01). There was no significant difference in overall survival (p > 0.05), or disease free survival (p > 0.05) between the two study arms. Adverse events were well matched between the two study arms. No Thromboembolic events associated with epoetin beta was observed in our study. Material and methods: Total 120, stage IIB to IIIB cervical cancer patients, aged 18-70 years with 9.50-12.50 g/dl baseline Hb value who were to receive radiotherapy together with cisplatin were randomized to receive either epoetin beta 10,000 IU thrice weekly and oral iron starting 10-15 days before their 5-week course of whole pelvic irradiation and weekly cisplatin (treatment arm) or standard supportive care (control arm), where epoetin beta was not given. Blood transfusion was given in patients of both the arms if hemoglobin was =10 g/dl. Conclusions: Treatment with epoetin beta safely and effectively corrects anemia in patients with advanced cervical cancer receiving chemoradiotherapy and is not associated with adverse effects on response rate, overall survival, disease free survival and chemoradiotherapy related acute and late toxicities.

Training the trainees in radiation oncology with telemedicine as a tool in a developing country: a two-year audit

Purpose. The estimated new cancer patient load in the Indian state of Uttar Pradesh is 0.1–0.12 million per year. Approximately two thirds of these require treatment by a radiation oncologist. Radiation oncologists: cancer patient ratio in this state is 1 : 2000 as compared to the recommended 1 : 250. This problem is compounded by the poor infrastructure of radiation oncology departments in the state which is suboptimal for teaching, training of resident doctors, and treatment in most barring a few departments. To bridge some gap in the sociodemographics stated above and enhancement of training of residents, we submitted a project for establishment of a telemedicine facility in our department to the Department of Science and Technology, Government of India. We present the design, implementation, and a two-year audit of our tele-education activities. Materials and Methods. After the sanction of the project, we established telemedicine linkage with another medical institute in the city located 25 kms away in 2007. After implementation of the project, academic sessions designed for trainee residents in our department were shared with the remote end. A record of these activities and a feedback of the activities were audited at the end of 2 years of implementation of this project. Results. Regular videoconferencing sessions comprising of lectures on clinical oncology, medical physics, and radiobiology were held. Feedback from the users revealed satisfaction with the content of the academic sessions for the purpose of MD training. Conclusions. Distance education in radiation oncology is an important tool for training of the trainee residents.