The Promise of Sonodynamic Therapy: Using Ultrasonic Irradiation and Chemotherapeutic Agents as a Treatment Modality

Sonodynamic therapy (SDT) is a potential cancer treatment modality that has been gaining support due to its effectiveness in both in vitro and in vivo studies. The therapeutic method combines ultrasonic irradiation with drugs known as sonosensitizers that amplify its ability to inflict preferential damage on malignant cells. This is based on the idea that ultrasonic waves have the ability to exhibit profound physical and chemical changes on cellular structure. The mechanisms by which ultrasound disrupts cellular functioning can be further amplified when sonosensitizers are applied. Combining multiple sonosensitizers with ultrasound to create a substantial synergistic effect could be an effective method for destroying tumorigenic growths, while decreasing the likelihood of drug resistance. Perhaps one of the most intriguing capabilities of ultrasound is its ability to preferentially lyse cells based on size. This known fact invariably gives rise to the idea of grossly enlarging tumor cells to increase their already noticeable size difference with normal cells. Cytochalasin B is a known pharmacological agent that disrupts the actin cytoskeleton and inhibits cytokinesis by interfering with formation of the contractile ring as well as the development of the cleavage furrow. Consequently, the cell does not divide and an immature actin cytoskeleton remains. However, the cell continues to form nuclei and eventually becomes grossly enlarged and multinucleated. Such cells invariably have more DNA targets, increasing the likelihood of apoptosis. Furthermore, the multinucleated cells have a large cell volume, making them more susceptible for direct cell destruction. Preferential damage of malignant cells is actually easily attainable as normal cells exposed to cytochalasin B exit the cell cycle and enter a resting state until sufficient actin levels are restored. Therefore, only malignant cells that have lost the ability to enter the rest phase will become grossly enlarged and multinucleated, providing an ideal target for ultrasonic irradiation. Work from our lab has indicated that cytochalasin B does indeed only damage leukemia cells, leaving normal blood cells, unaffected. The designated cell line has been promyleocytic leukemia U937 cells as they are a frequent choice for in vitro studies. The U937 cells have routinely become grossly enlarged and multinucleated, providing an ideal target based on size. The typical erythrocyte is 6-8µm, while leukocytes fair slightly better with a range of 10-15µm and an average of 12µm. By contrast, work from our lab has shown that cytochalasin B treated leukemia cells easily grow in excess of 20µm with some reaching 40µm in diameter after enough exposure. Such cells have reduced cytoskeletal integrity and are easy targets for ultrasonic irradiation. Furthermore, cytochalasin B treated leukemia cells are substantially multinucleated as cytokinesis is inhibited. This provides plenty of targets for a nucleic acid directed agent such as cisplatin or doxorubicin to attack. To investigate the extent of preferential damage inflicted by cytochalasin B on U937 leukemia/human blood populations, cell mixtures were treated with cytochalasin B and then sonicated under a relatively low intensity (3W/cm2). Results indicated that cytochalasin B preferentially damages U937 cells both before and after sonications. The agent also demonstrates the capability to eliminate rapid proliferation as U937 cells have a marked decrease in clonogenicity. Such findings suggest that cytochalasin B may have profound therapeutic applications when combined with SDT. Key Words Sonodynamic Therapy, Ultrasound, Sonosensitizers, Inertial Cavitation, Reactive Oxygen Species, Tumor Vasculature, Preferential Damag

A Cross-Disciplinary Examination of Institutional Diversity: How University Programs Advance a Diverse Workforce

Diversity in higher education is encouraged and celebrated throughout many predominant universities across the United States. Institutions of higher learning benefit from diversity in all aspects of campus life; from classes, organizations, or extracurricular activities. Institutional theory is applied to this study to examine how diversity programs are implemented in various university types (national research, private, and state) as well as different settings (educational opportunities, leadership, and accessibility) to develop a qualified and diverse workforce. To achieve this objective, we suggest universities implement a multifaceted approach focusing on initiatives at the university, faculty, and student level

Genetic and Modifiable Risk Factors Contributing to Cisplatin-Induced Toxicities

Effective administration of traditional cytotoxic chemotherapy is often limited by off-target toxicities. This clinical dilemma is epitomized by cisplatin, a platinating agent that has potent antineoplastic activity due to its affinity for DNA and other intracellular nucleophiles. Despite its efficacy against many adult-onset and pediatric malignancies, cisplatin elicits multiple off-target toxicities that can not only severely impact a patient’s quality of life, but also lead to dose reductions or the selection of alternative therapies that can ultimately affect outcomes. Without an effective therapeutic measure by which to successfully mitigate many of these symptoms, there have been attempts to identify a priori those individuals who are more susceptible to developing these sequelae through studies of genetic and nongenetic risk factors. Older age is associated with cisplatin induced ototoxicity, neurotoxicity and nephrotoxicity. Traditional genome-wide association studies have identified single nucleotide polymorphisms in ACYP2 and WFS1 associated with cisplatin-induced hearing loss. However, validating associations between specific genotypes and cisplatin-induced toxicities with enough stringency to warrant clinical application remains challenging. This review summarizes the current state of knowledge with regard to specific adverse sequelae following cisplatin-based therapy with a focus on ototoxicity, neurotoxicity, nephrotoxicity, myelosuppression and nausea/emesis. We discuss variables (genetic and nongenetic) contributing to these detrimental toxicities, and currently available means to prevent or treat their occurrence

Clinical and Genome-Wide Analysis of Serum Platinum Levels after Cisplatin-Based Chemotherapy

Purpose: Serum platinum is measurable for years after completion of cisplatin-based chemotherapy (CBC). We report the largest investigation of serum platinum levels to date of 1,010 testicular cancer survivors (TCS) assessed 1-35 years after CBC and evaluate genetic contributions to these levels. Experimental Design: Eligible TCS given 300 or 400 (±15) mg/m2 cisplatin underwent extensive audiometric testing, clinical examination, completed questionnaires and had crude serum platinum levels measured. Associations between serum platinum and various risk factors and toxicities were assessed after fitting a bi-exponential model adjusted for follow-up time and cumulative cisplatin dose. A genome-wide association study (GWAS) was performed using the serum platinum residuals of the dose and time-adjusted model. Results: Serum platinum levels exceeded the reference range for approximately 31 years, with a strong inverse relationship with creatinine clearance at follow-up (age-adjusted p = 2.13×10−3). We observed a significant, positive association between residual platinum values and luteinizing hormone (age-adjusted p=6.58×10−3). Patients with high residual platinum levels experienced greater Raynaud’s phenomenon than those with medium or low levels (age-adjusted ORhigh/low = 1.46; p = 0.04), as well as a higher likelihood of developing tinnitus (age-adjusted ORhigh/low = 1.68, p = 0.07). GWAS identified one single nucleotide polymorphism (SNP) meeting genome-wide significance rs1377817 (p=4.6×10−8, a SNP intronic to MYH14). Conclusions: This study indicates that residual platinum values are correlated with several cisplatin-related toxicities. One genetic variant is associated with these levels

Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms

Cisplatin, a commonly used chemotherapeutic, results in tinnitus, the phantom perception of sound. Our purpose was to identify the clinical and genetic determinants of tinnitus among testicular cancer survivors (TCS) following cisplatin-based chemotherapy. Experimental Design: TCS (n= 762) were dichotomized to cases (moderate/severe tinnitus; n=154) and controls (none; n=608). Logistic regression was used to evaluate associations with comorbidities and SNP dosages in GWAS following quality control and imputation (covariates: age, noise exposure, cisplatin dose, genetic principal components). Pathway over-representation tests and functional studies in mouse auditory cells were performed. Results: Cisplatin-induced tinnitus (CisIT) significantly associated with age at diagnosis (P=0.007) and cumulative cisplatin dose (P=0.007). CisIT prevalence was not significantly greater in 400 mg/m2-treated TCS compared to 300 (P=0.41), but doses >400 mg/m2 (median 580, range 402–828) increased risk by 2.61-fold (P<0.0001). CisIT cases had worse hearing at each frequency (0.25–12 kHz, P<0.0001), and reported more vertigo (OR=6.47; P<0.0001) and problems hearing in a crowd (OR=8.22; P<0.0001) than controls. Cases reported poorer health (P=0.0005) and greater psychotropic medication use (OR=2.4; P=0.003). GWAS suggested a variant near OTOS (rs7606353, P=2×10−6) and OTOS eQTLs were significantly enriched independently of that SNP (P=0.018). OTOS overexpression in HEI-OC1, a mouse auditory cell line, resulted in resistance to cisplatin-induced cytotoxicity. Pathway analysis implicated potassium ion transport (q=0.007). Conclusions: CisIT associated with several neuro-otological symptoms, increased use of psychotropic medication, and poorer health. OTOS, expressed in the cochlear lateral wall, was implicated as protective. Future studies should investigate otoprotective targets in supporting cochlear cells