Normal Tissue Protection Research Articles

136 Simultaneous normal tissue protection and increased tumor radiosensitivity : A new goal for pravastatin?

136 Simultaneous normal tissue protection and increased tumor radiosensitivity : A new goal for pravastatin?

937. Radioprotection of Normal Tissue Cells by Transfer of the Human Superoxide-Dismutase Gene

Background: Protection of normal tissue against radiation- induced damage would increase the therapeutic ratio of radiotherapy. A promising strategy for this approach is gene therapy-mediated overexpression of copper-zinc (CuZnSOD) and manganese superoxide-dismutase (MnSOD). Recombinant adeno-associated virus 2 (rAAV2) are attractive vectors owing to their ability to infect non-dividing cells and a very low risk of insertional mutagenesis. The purpose was to test the radio-modulating effects of SOD on human primary lung fibroblasts (HPLF).

Targeting Molecular Determinants of Tumor Chemo-Radioresistance

Attempts to improve results of chemoradiotherapy by increasing the total dose of radiation or chemotherapy or by changing chemotherapeutic drugs have not been very successful. Additionally, some combinations have been associated with a high rate of unacceptable treatment-related morbidity, underscoring the need for new treatment strategies to combine with radiation to improve the therapeutic ratio. Potentially useful strategies include the selective protection of normal tissues, interference with resistance mechanisms, improved targeting of tumor stem cells, and dealing with residual tumor disease. Evidence is mounting that epidermal growth factor receptor (EGFR) overexpression or mutation, as well as dysregulation in cyclins and cyclin-dependent kinases represent major determinants in aggressive tumor growth and poor tumor response to standard treatment modalities, including radiotherapy. Two major approaches have been investigated, one consisting of blocking the extracellular domain of the receptor with anti-EGFR antibodies to prevent ligand-receptor binding, and the other consisting of small chemical compounds, tyrosine kinase inhibitors, which bind to the intracellular domain of the receptor preventing its phosphorylation. Clinical trials are evaluating whether or not quantifying EGFR expression in tumors can serve as a predictor of treatment outcome and if the incorporation of EGFR inhibitors into radiotherapy can improve treatment outcome.

A Potential Synergistic Anticancer Effect of Paclitaxel and Amifostine on Endometrial Cancer

Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 micromol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G2-M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated.

1353 ORAL Normal tissue protection and modulation of tumor radiation sensitivity by the combination of pravastatin with radiotherapy

1353 ORAL Normal tissue protection and modulation of tumor radiation sensitivity by the combination of pravastatin with radiotherapy

Amifostine for Xerostomia - Normal Tissue Protection at What Cost?

Purpose/Objective: Amifostine reduces xerostomia in patients receiving head and neck radiotherapy (RT) but is associated with significant toxicity and cost. In this retrospective review we compared records of patients irradiated with and without amifostine for grades of acute xerostomia, mucositis, drug-related toxicity, as well as drug cost and disease outcomes.

Is intensity-modulated radiotherapy better than conventional radiation treatment and three-dimensional conformal radiotherapy for mediastinal masses in patients with Hodgkin’s disease, and is there a role for beam orientation optimization and dose constraints assigned to virtual volumes?

To evaluate the role of beam orientation optimization and the role of virtual volumes (VVs) aimed at protecting adjacent organs at risk (OARs), and to compare various intensity-modulated radiotherapy (IMRT) setups with conventional treatment with anterior and posterior fields and three-dimensional conformal radiotherapy (3D-CRT). Patients with mediastinal masses in Hodgkin's disease were treated with combined modality therapy (three to six cycles of adriamycin, bleomycin, vinblastine, and dacarbazine [ABVD] before radiation treatment). Contouring and treatment planning were performed with Somavision and CadPlan Helios (Varian Systems, Palo Alto, CA). The gross tumor volume was determined according to the prechemotherapy length and the postchemotherapy width of the mediastinal tumor mass. A 10-mm isotropic margin was added for the planning target volume (PTV). Because dose constraints assigned to OARs led to unsatisfactory PTV coverage, VVs were designed for each patient to protect adjacent OARs. The prescribed dose was 40 Gy to the PTV, delivered according to guidelines from International Commission on Radiation Units and Measurements Report No. 50. Five different IMRT treatment plans were compared with conventional treatment and 3D-CRT. Beam orientation was important with respect to the amount of irradiated normal tissues. The best compromise in terms of PTV coverage and protection of normal tissues was obtained with five equally spaced beams (5FEQ IMRT plan) using dose constraints assigned to VVs. When IMRT treatment plans were compared with conventional treatment and 3D-CRT, dose conformation with IMRT was significantly better, with greater protection of the heart, coronary arteries, esophagus, and spinal cord. The lungs and breasts in women received a slightly higher radiation dose with IMRT compared with conventional treatments. The greater volume of normal tissue receiving low radiation doses could be a cause for concern. The 5FEQ IMRT plan with dose constraints assigned to the PTV and VV allows better dose conformation than conventional treatment and 3D-CRT, notably with better protection of the heart and coronary arteries. Of concern is the "spreading out" of low doses to the rest of the patient's body.

Implications for Tumor Control During Protection of Normal Tissues With Antioxidants

The use of antioxidants during antineoplastic radiation therapy has long been a controversial topic. Antioxidants are known for their ability to scavenge free radicals, potentially reducing the damage caused by ionizing radiation to treated tissues. Reduction of normal tissue injury from radiotherapy with antioxidant supplementation is intriguing; however, it raises significant concerns about the possible inadvertent simultaneous protection of tumor tissues. This issue is not limited to the clinical trial setting, given that increasing numbers of the American public take vitamin supplements and naturopathic remedies during therapy. DNA damage is the most lethal form of cellular damage caused by ionizing radiation. With the types of ionizing radiation used in clinical practice today, approximately two thirds of DNA damage is caused by short-lived (nanoseconds to microseconds) high-energy primary and secondary free radicals. To act as a radioprotector by scavenging these free radicals, an antioxidant needs to be present in sufficient concentrations and have efficient radical scavenging capabilities in proximity to the target (DNA) during the radiation exposure. -tocopherol and -carotene would not be expected to provide significant protection against radiationinduced primary and secondary reactive species compared with conventional radioprotectors. However, free-radical generation in tissues may continue after the radiation exposure as a consequence of an inflammatory response, with the generation of cytokines and sustained production of longer lived free radicals. In this setting, particularly in normal tissues, -tocopherol and -carotene may in fact be quite effective toward protecting against sustained freeradical damage. Interestingly, it is now becoming clear that free radicals can also serve as initiators (triggers) for complex signal transduction and gene expression pathways governing proand antisurvival responses. For example, -tocopherol can modulate transcriptional and posttranscriptional regulation of protein kinase C, cyclooxigenase, and lipoxygenase. Whether radiation induces a similar inflammatory response in tumors is less clear, given their markedly different redox status. To further complicate the issue of supplementation, the concentration of the agent or the surrounding environment can alter the antioxidant effects of many molecules. As for the microenvironment, -carotene is an antioxidant at low oxygen concentrations; however, it acts as a pro-oxidant at high oxygen concentrations. To illustrate this complex relationship of dose, agent, and microenvironment, consider the following two large randomized studies that have assessed the efficacy of -carotene as a preventative agent in patients at high risk of malignancy. The Alpha-Tocopherol, Beta-Carotene cancer prevention trial randomly assigned 29,133 male smokers to supplementation with -tocopherol, -carotene, both, or placebo, and unexpectedly found an increased risk of lung cancer in participants who received -carotene supplementation. Supplementation with -tocopherol alone in this study appeared to have no adverse effect on lung cancer incidence. In addition, the -Carotene and Retinol Efficacy trial randomly assigned 18,314 men and women at high risk of developing lung cancer to the combination of daily -carotene and retinyl palmitate (vitamin A) or placebo. This large study was stopped early because of evidence of a significant increase in the risk of lung cancer and lung cancer mortality in the treatment group compared with the placebo group. It is hypothesized that the increased incidence of lung cancers seen in both of these large, randomized studies is at least partially due to the pro-oxidant nature of -carotene when used at high doses or in oxygen-rich environments, such as the lung. How do the preclinical findings that antioxidants improve the efficacy of radiotherapy translate into clinical outcomes? Numerous clinical studies investigating the effects of antioxidants in combination with radiotherapy or JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 24 AUGUST 2

DNA damage response pathways in cancer causation and treatment

DNA damage response pathways in cancer causation and treatment

Intensity modulated radiation therapy (IMRT) for nasopharynx cancer: Update of the Memorial Sloan-Kettering experience

5541 Background: We previously demonstrated that IMRT significantly improves radiation dose distribution over 3-dimensional (3D) planning for nasopharynx cancer (NPC) and reported positive early clinical results. We now evaluate whether IMRT has resulted in improved outcomes for a larger cohort of NPC patients with longer follow-up. Methods: Since 1998, all 74 patients with newly diagnosed, nonmetastatic NPC were treated with IMRT using accelerated fractionation to 70 Gy; 59 received a hyperfractionated concomitant boost and more recently 15 received once daily treatment with dose-painting. With the exception Stage I disease (n=5) and patient refusing (n=1), 69 patients received concurrent and adjuvant platinum based chemotherapy similar to Intergroup 0099 trial. Results: Patient characteristics: median age 45; 32% Asian; 72% male; 65% WHO III; 51% Stage T3/4, 47% N2/3, and 47% Stage IV. Median follow up is 33 months. The 3-year actuarial rate of local control is 89% and regional control is 95%. Freedom from distant metastases, progression-free survival, and overall survival are 78%, 64% and 82% respectively. Six of the seven local failures were exclusively within the 70Gy volume and one was both within and outside the target volume. There is a trend for improved local control with IMRT when compared to local control of 79% for patients treated prior to 1998 with 3D planning and chemotherapy, but this is not statistically significant (p=0.18). Six months post-therapy, 21%, 13%, 15% and 0% of patients with follow-up audiograms (n=24 patients, 48 ears) had Grade 1, 2, 3, and 4 sensorineural hearing loss, respectively. For patients with >1 year follow-up (n=59), rates of long-term xerostomia were: 26% none, 42% grade 1, 32% grade 2, and zero grade 3. Conclusions: The lack of significant improvement in local control with IMRT and pattern of primary site failure within the target volume suggest a need for a higher biological dose to gross tumor. Rates of severe (grade 3–4) ototoxicity and xerostomia are low with IMRT due to normal tissue protection. Distant metastases are now the dominant form of failure emphasizing the need for improved systemic therapy. No significant financial relationships to disclose.

Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: Update of the Memorial Sloan-Kettering experience

We previously demonstrated that intensity-modulated radiation therapy (IMRT) significantly improves radiation dose distribution over three-dimensional planning for nasopharynx cancer and reported positive early clinical results. We now evaluate whether IMRT has resulted in improved outcomes for a larger cohort of patients with longer follow-up. Since 1998, all 74 patients with newly diagnosed, nonmetastatic nasopharynx cancer were treated with IMRT using accelerated fractionation to 70 Gy; 59 received a hyperfractionated concomitant boost, and more recently 15 received once-daily treatment with dose painting. With the exception of Stage I disease (n = 5) and patient preference (n = 1), 69 patients received concurrent and adjuvant platinum-based chemotherapy similar to that in the Intergroup 0099 trial. median age 45; 32% Asian; 72% male; 65% World Health Organization III; 6% Stage I, 16% Stage II, 30% Stage III, 47% Stage IV. Median follow-up is 35 months. The 3-year actuarial rate of local control is 91%, and regional control is 93%; freedom from distant metastases, progression-free survival, and overall survival at 3 years are 78%, 67%, and 83%, respectively. There was 100% local control for Stage T1/T2 disease, compared to 83% for T3/T4 disease (p = 0.01). Six patients failed at the primary site, with median time to local tumor progression 16 months; 5 were exclusively within the 70 Gy volume, and 1 was both within and outside the target volume. There is a trend for improved local control with IMRT when compared to local control of 79% for 35 patients treated before 1998 with three-dimensional planning and chemotherapy (p = 0.11). Six months posttherapy, 21%, 13%, 15%, and 0% of patients with follow-up audiograms (n = 24 patients) had Grade 1, 2, 3, and 4 sensorineural hearing loss, respectively. For patients with >1 year follow-up (n = 59), rates of long-term xerostomia were as follows: 26% none, 42% Grade 1, 32% Grade 2, and zero Grade 3. The pattern of primary site failure within the target volume suggests locally advanced T stage disease may require a higher biologic dose to gross tumor. Rates of severe (Grade 3-4) ototoxicity and xerostomia are low with IMRT as a result of normal-tissue protection. Distant metastases are now the dominant form of failure, emphasizing the need for improved systemic therapy.

131. Recombinant Adeno-Associated Virus 2-Mediated Transfer of the Human Superoxide-Dismutase Gene Does Not Confer Radioresistance on HeLa Cervical Carcinoma Cells

Top of pageAbstract Introduction: The success rate of any therapeutic approach depends on the therapeutic window, which can be increased by either raising the resistance of the normal tissue without protecting the tumor cells or by sensitizing the tumor cells but not the normal cells. Two promising candidate genes for normal tissue protection against radiation-induced damage may be the copper-zinc (CuZnSOD) and manganese superoxide-dismutase genes (MnSOD). The recombinant adeno-associated virus 2 (rAAV-2) offers attractive advantages over other vector systems: low immunogenicity, ability to infect dividing and non-dividing tissues and a low chance of insertional mutagenesis, due to extra-chromosomal localization. We report the production of novel rAAV-2-SOD vectors and the investigation of their modulating effects on HeLa-RC cells after irradiation. Material and methods: rAAV-2 vectors were cloned containing the human CuZnSOD or MnSOD as transgene and vector stocks were produced. In the initial experiments human cervix carcinoma (HeLa-RC) cells were chosen for their susceptibility to rAAV-2. On day 0, cells were seeded and transduced with the rAAV-2-SOD vectors. On day 3, cells were harvested, irradiated (1-8 Gy) and reseeded in different assays (FACS, SOD, MTT and colony assays). Furthermore, a proliferation assay was performed on SOD-transduced cells which were incubated with the superoxide radical-generating substance paraquat for 96 hours, in order to show the functionality of the SOD vectors. Results: Although >70% of all cells expressed SOD, significant amounts of SOD protein were detected and the superoxide-detoxifying function of SOD could be shown, no radioprotective effect of SOD was observed after transduction of HeLa-RC cells. Conclusions: Novel rAAV-2-SOD vectors that could be produced at high titer, were able to efficiently infect cells and express functional SOD. The absence of a radioprotective effect in the HeLa-RC cancer cells indicates an additional safety feature and suggests that rAAV-mediated MnSOD overexpression might contribute to increasing the therapeutic index when applied for normal tissue protection. AAV-SOD radioprotection studies on normal tissue cells are currently in progress.

Protection of Mouse Bone Marrow against Radiation-Induced Chromosome Damage and Stem Cell Death by the Ocimum Flavonoids Orientin and Vicenin

In a previous study, orientin and vicenin, the water-soluble plant flavonoids, protected mice against radiation lethality (Uma Devi et al., Radiat. Res. 151, 74-78, 1999). To study bone marrow protection, adult Swiss mice were exposed to 0-6 Gy 60Co gamma rays 30 min after an intraperitoneal injection of 50 microg/ kg body weight of orientin/vicenin. Chromosomal aberrations in bone marrow were studied at 24 h postirradiation. Stem cell survival was studied using the exogenous spleen colony (CFU-S) assay. Radiation produced a dose-dependent increase in aberrant cells as well as in the yield of the different types of aberrations (breaks, fragments, rings and dicentrics) and a decrease in CFU-S. Pretreatment with either flavonoid significantly reduced the aberrant cells and different aberrations and increased the number of CFU-S compared to the respective radiation-alone groups. The dose modification factors for 50% reductions in the number of CFU-S were 1.6 for orientin and 1.7 for vicenin. The present finding that very low nontoxic doses of orientin and vicenin provide efficient protection against bone marrow damage at clinically relevant radiation doses suggests their potential for protection of normal tissues in radiotherapy.

Analysis of Common Single Nucleotide Polymorphisms in MDR1 Gene in Patients with Multiple Myeloma.

P-glycoprotein (P-gp) encoded by MDR1 gene is a xenobiotic transporter involved in protection of normal tissues against environmental toxicants and multi-drug resistance of cancer cells. Recently, a number of authors, including our group, have indicated that phenomenon of single nucleotide polymorphism (SNP) in MDR1 may influence susceptibility or prognosis in various diseases as well as pharmacokinetics of P-gp substrates. Although environmental chemicals are suspected carcinogens in multiple myeloma (MM) and P-gp transported drugs are used in the treatment of this malignancy, little data is known on the significance of MDR1 SNPs in MM. In this study, three common MDR1 SNPs: C1236T, G2677T/A and C3435T were assessed in 89 MM patients using automated sequencing and RFLP method. Moreover, in the control group of 215 healthy individuals MDR1 C3435T SNP was genotyped in all subjects and P-gp expression and activity were examined in a proportion of subjects. The haplotypes were inferred using Partition-Ligation algorithm showing highest frequency of the haplotype with wild-type alleles at all sites studied (1236C-2677G-3435C, 30%), followed by haplotype with all mutant alleles (1236T-2677T-3435T; 27%) and 1236C-2677G-3435T haplotype (12%). Carriers of a mutant allele at MDR1 1236 site showed a trend to longer overall survival as compared to wild-type homozygotes MDR1 1236CC (p=0.08), while no correlations with survival were observed regarding other polymorphisms. As compared to the control group, the MDR1 C3435T SNP allele frequency did not differ in MM patients, however the carriers of at least one T-allele (CT and TT genotypes) were significantly more frequent in the MM cohort (79% vs. 65%, p=0.02). The flow cytometry results of anti-P-gp MRK16 antibody staining and functional rhodamin123/PSC833 assay performed on peripheral blood mononuclear cells, CD19+ B-lymphocytes and CD3+ T-lymphocytes were similar among healthy individuals having MDR1 3435CC, CT and TT genotypes. In conclusion, we observed that MDR1 gene SNPs may exert some effect in genetic predisposition and prognosis in MM, which should be further examined in larger cohorts of uniformly treated patients.

An Novel Approach in Protective Gene Therapy: Recombinant Adeno-Associated Virus 2-Mediated Transfer of the Human Superoxide-Dismutase Gene.

Background and purpose: The success rate of any therapeutic approach depends on the therapeutic window, which can be increased by either raising the resistance of the normal tissue such as hematopoietic cells without protecting the tumor cells or by sensitizing the tumor cells but not the normal cells. Two promising candidate genes for normal tissue protection against superoxide-induced damage may be the copper-zinc (CuZnSOD) and manganese superoxide-dismutase genes (MnSOD). Oxidative stress-induced apoptosis plays a role in both radiation- and chemotherapy-induced tissue damage. Relevant cytostatic drugs for which oxidative stress as one mechanism of action has been described are e.g. anthracyclins, platinum analogues, etoposide and ara-C. For gene therapeutic approaches, recombinant adeno-associated virus 2 (rAAV-2)-based vectors offer attractive advantages over other vector systems: low immunogenicity, possibility of in vivo application, ability to infect dividing and non-dividing tissues and a low chance of insertional mutagenesis, due to extra-chromosomal localization. Here, we report the production and testing of novel rAAV-2-SOD vectors with the goal of normal tissue protection.Material and methods: Various rAAV-2 vectors containing CuZnSOD, MnSOD and fusion proteins of both with the enhanced green fluorescent protein (eGFP) gene were cloned and vector stocks were produced. Human cervix carcinoma (HeLa-RC) cells were chosen for their susceptibility to rAAV-2. Cells were seeded and transduced with the rAAV-2-SOD vectors. Gene transfer and transgene expression were investigated using FACS and an SOD-activity assay.Results: Over 70% of all HeLa cells expressed SOD and significant amounts of functional SOD protein were detected (table 1).Conclusion: These results forms the basis to evaluate the radio- and chemoprotective effects of AAV-mediated SOD gene therapy in hematopoietic and non-hematopoietic (e.g. mucosal) cells.Vector% GFP+ cellsSOD activity (U/mg)Mock control-435 ± 37rAAV-2-CuZnSODN/A965 ± 112rAAV-2-CuZnSOD/eGFP78 ± 21093 ± 178rAAV-2-MnSODN/A1516 ± 191rAAV-2-MnSOD/eGFP77 ± 31204 ± 124

128 Normal tissue protection by Bowman-Birk proteinase inhibitor and phospho-tyrosine

128 Normal tissue protection by Bowman-Birk proteinase inhibitor and phospho-tyrosine

Combining gene therapy and radiation against cancer.

Radiation has been a well-established modality in cancer treatment for several decades. Significant improvements have been achieved in radiotherapy over the years due to technological advances and development of facilities for delivery of charged particles such as protons. Nonetheless, the potential for tumor control with radiotherapy must always be carefully balanced with the risk for normal tissue damage. In addition, tumor cells outside the immediate field of radiation exposure or that have metastasized to distant sites are not destroyed. Gene therapy offers many exciting possibilities by which the overall efficacy of radiotherapy may be improved, while minimizing unwanted side effects. This review highlights several of the most promising gene transfer approaches that are currently being evaluated in combination with radiation in the treatment of cancer. Results from studies utilizing genes encoding molecules that function in apoptosis, radiosensitization, immune up-regulation, angiogenesis, DNA repair, normal tissue protection from radiation damage, and tumor targeting are discussed. The evidence indicates that many of these innovative gene-based strategies have great potential to augment radiotherapy, as well as other established forms of cancer treatment, in the near future.

Recombinant adeno-associated virus 2-mediated transfer of the human superoxide-dismutase gene does not confer radioresistance on HeLa cervical carcinoma cells

Background and purpose The success rate of any therapeutic approach depends on the therapeutic window, which can be increased by either raising the resistance of the normal tissue without protecting the tumor cells or by sensitizing the tumor cells but not the normal cells. Two promising candidate genes for normal tissue protection against radiation-induced damage may be the copper–zinc (CuZnSOD) and manganese superoxide-dismutase genes (MnSOD). The recombinant adeno-associated virus 2 (rAAV-2) offers attractive advantages over other vector systems: low immunogenicity, ability to infect dividing and non-dividing tissues and a low chance of insertional mutagenesis, due to extra-chromosomal localization. We report the production of novel rAAV-2-SOD vectors and the investigation of their modulating effects on HeLa-RC cells after irradiation. Material and methods rAAV-2 vectors were cloned containing the human CuZnSOD or MnSOD as transgene and vector stocks were produced. In the initial experiments human cervix carcinoma (HeLa-RC) cells were chosen for their susceptibility to rAAV-2. On day 0, cells were seeded and transduced with the rAAV-2-SOD vectors. On day 3, cells were harvested, irradiated (0.5–8 Gy) and reseeded in different assays (FACS, SOD, MTT and colony assays). Results Although >70% of all cells expressed SOD and significant amounts of functional SOD protein were detected, no radioprotective effect of SOD was observed after transduction of HeLa-RC cells. Conclusions Novel rAAV-2-SOD vectors that could be produced at high titer, were able to efficiently infect cells and express the SOD genes. The absence of a radioprotective effect in HeLa-RC cancer cells indicates an additional safety feature and suggests that rAAV-mediated MnSOD overexpression might contribute to increasing the therapeutic index when applied for normal tissue protection.

Chemotherapy-induced peripheral neuropathy: pathogenesis and emerging therapies.

Peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutic agents. The type and degree of neuropathy depend on the chemotherapy drug, dose-intensity, and cumulative dose. Disabling peripheral neuropathy has a significant negative impact on quality of life. Accordingly, a reliable assessment of chemotherapy-induced peripheral neurotoxicity is necessary, especially if potential neuroprotective agents are to be investigated. Chemoprotectants are agents that have been developed to ameliorate the toxicity associated with cytotoxic drugs. They aim to provide site-specific protection for normal tissues, without compromising antitumor efficacy. Several chemoprotectant compounds have been studied in recent clinical trials. These trials must include sufficient dose-limiting events for study and assessment of both toxicity and antitumor effect. A future avenue of investigation includes the identification of patients at higher risk for the development of peripheral neuropathy based on their genotype. Identification of these higher-risk patients may enable us to devise prevention strategies prior to the onset of this potentially debilitating complication.

Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts.

Studies were carried out in athymic nude mice bearing human squamous cell carcinoma of the head and neck (FaDu and A253) and colon carcinoma (HCT-8 and HT-29) xenografts to evaluate the potential role of selenium-containing compounds as selective modulators of the toxicity and antitumor activity of selected anticancer drugs with particular emphasis on irinotecan, a topoisomerase I poison. Antitumor activity and toxicity were evaluated using nontoxic doses (0.2 mg/mouse/day) and schedule (14-28 days) of the selenium-containing compounds, 5-methylselenocysteine and seleno-L-methionine, administered orally to nude mice daily for 7 days before i.v. administration of anticancer drugs, with continued selenium treatment for 7-21 days, depending on anticancer drugs under evaluation. Several doses of anticancer drugs were used, including the maximum tolerated dose (MTD) and toxic doses. Although many chemotherapeutic agents were evaluated for toxicity protection by selenium, data on antitumor activity were primarily obtained using the MTD, 2 x MTD, and 3 x MTD of weekly x4 schedule of irinotecan. Selenium was highly protective against toxicity induced by a variety of chemotherapeutic agents. Furthermore, selenium increased significantly the cure rate of xenografts bearing human tumors that are sensitive (HCT-8 and FaDu) and resistant (HT-29 and A253) to irinotecan. The high cure rate (100%) was achieved in nude mice bearing HCT-8 and FaDu xenografts treated with the MTD of irinotecan (100 mg/kg/week x 4) when combined with selenium. Administration of higher doses of irinotecan (200 and 300 mg/kg/week x 4) was required to achieve high cure rate for HT-29 and A253 xenografts. Administration of these higher doses was possible due to selective protection of normal tissues by selenium. Thus, the use of selenium as selective modulator of the therapeutic efficacy of anticancer drugs is new and novel. We demonstrated that selenium is a highly effective modulator of the therapeutic efficacy and selectivity of anticancer drugs in nude mice bearing human tumor xenografts of colon carcinoma and squamous cell carcinoma of the head and neck. The observed in vivo synergic interaction is highly dependent on the schedule of selenium.