Thesis (M.S.)--Kent State University, 2008. / Title from PDF t.p. (viewed May 21, 2009). Advisor: John R.D. Stalvey. Keywords: ovarian cancer, progesterone, cisplatin. Includes bibliographical references (p. 67-75).

No description available.

This study aimed to evaluate the efficacy of different treatment modifications used to prevent or minimise hearing loss during Cisplatin-based chemotherapy as part of patient management at Groote Schuur Hospital. The study also sought to compare different ototoxicity grading criteria; namely the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4 (CTCAE v4) and TUNE criteria, with respect to early identification of changes in the patient’s hearing thresholds following treatment with ototoxic drugs as well as ability to guide recommendations for aural rehabilitation including hearing amplification. Background Non-communicable diseases (NCD) (including cancer, diabetes, cardiovascular and chronic respiratory diseases) are responsible for an estimated 36 million deaths annually across the world. Approximately 80 % of these deaths occur in developing countries. Cancer, the NCD of interest in this study, causes an estimated 8.2 million deaths per year, globally and about 70 % of these occur in developing countries. In South Africa, cancer is estimated to cause approximately 40 000 deaths per annum, which is more than the number of deaths caused by a combination of HIV/AIDS, TB and malaria every year. Cisplatin is the most common and effective anti-cancer drug for most types of cancers. However, it is also associated with severe adverse effects, including hearing loss. Cisplatin-induced hearing loss is usually bilateral, highfrequency sensorineural hearing loss and is permanent. Cisplatin-induced hearing loss can lead to communication difficulties, lack of participation, loss of employment and social isolation. This decreases patients’ quality of life. Prevention of ototoxicity relies on serial audiologic monitoring to detect any significant change in patients’ hearing thresholds that may be resulting from chemotherapy treatment. When a deterioration in the patient’s hearing thresholds is detected, treating physician(s) can decide on whether to modify the patient’s treatment to prevent further deterioration of hearing or not. Some of the common treatment modifications used by physicians include; reducing the drug dose administered to the patient, changing from Cisplatin to a less ototoxic drug such as Carboplatin or keeping a patient on Cisplatin only regimen (no treatment modification). However, there is 8 currently lack of research evidence that document the effectiveness of these treatment modifications with respect to preservation of the patient’s hearing thresholds. Also, given that there are several ototoxicity grading scales available that can be used to grade severity of ototoxicity-induced hearing loss, there is currently a lack of uniformity regarding communication of the severity of hearing loss across different professionals. There is a need to identify or develop an ototoxicity grading criterion which can be adopted by different professionals to communicate results during ototoxicity monitoring of patients. Research design This study employed a descriptive, quantitative retrospective cohort design. Medical folders of patients who underwent cisplatin chemotherapy treatment and had their hearing thresholds monitored at Groote Schuur Hospital during from 2011 up to 2016 were reviewed. Methods A non-probability, convenience sampling method was used to select medical folders that underwent review. Data which were extracted from the patients’ medical folders includes demographic information (for example age and sex,), chemotherapy treatment information including type and dose of treatment; and audiological information including baseline, checkup and exit audiogram thresholds. Data obtained from the folders were analysed using R, a software environment for statistical computing and graphics. Descriptive statistics and the following inferential statistical tests, Chi-squared, Fisher’s exact tests and the Wilcoxon signed-rank test for paired samples, were used to determine significant associations between hearing loss and several factors revealed in the data. The American Speech-Language and Hearing (ASHA, 1994) criteria were used to determined incidence of significant threshold shift whilst the CTCAE v4 was used to determine both incidence of hearing loss and severity of the loss. The CTCAE v4 and TUNE criteria were compared based on incidence of hearing and ability to predict need for hearing amplification Results A total of 128 medical folders met inclusion criteria for this study and the following were the patient characteristics; median age = 43 years (range: 18 – 75 years); 92 males, 36 females; average length on treatment: 13.45 weeks). Out of these, 64 had information on the type and dose information of chemotherapy drug used during the period when monitoring of ototoxicity was conducted. The American Speech-Language and Hearing (ASHA) criteria revealed 9 ototoxicity in 74.2 % (95/128) of the sample. The Wilcoxon signed-rank test for paired samples showed a significant difference (p = 0.0000000039, p < 0.05) between follow-up and exit monitoring thresholds which indicated a significant decline of patients’ hearing thresholds throughout the treatment duration. There were no statistically significant associations between age, duration of treatment and treatment modification. The study showed three treatment modifications which included dose adjustment (reduction), switching drug and continuing with the same drug. There was no significant association between treatment modifications and hearing loss. The CTCAEv4 criteria identified more people (53.9 %) who experienced a deterioration in their hearing thresholds than TUNE criteria (41.7%). However, TUNE performed better with respect to identifying patients who are likely to be candidates for further audiological rehabilitation including hearing amplification. Conclusion This study found a high incidence of cisplatin-induced hearing loss despite the possible modification of treatment. This shows that current strategies that are used by physicians at GSH Radiation Oncology department to prevent or minimize further deterioration of the patient’s hearing thresholds during cisplatin chemotherapy can arguably be rendered ineffective. This is owing to the inability of conventional audiometry to detect hearing loss before it affects the speech frequencies. There was no significant association between hearing loss and age, dose, duration of treatment and treatment modification. The study also showed that CTCAE v4 grading criteria detected a higher incidence of ototoxicity than the TUNE criteria. However, the TUNE criteria were better at detecting the number of patients who need further audiological rehabilitation than the CTCAE v4. Therefore, both scales have their strengths and weaknesses. Implications of the study include the incorporation of Extended High Frequency Audiometry (EHF) and Distortion Product Otoacoustic Emission (DPOAE) testing into the monitoring protocol where possible to allow for early detection and intervention of ototoxicity. Incorporation of otoprotectors into the prevention protocol is suggested as they have recently shown otoprotective efficacy in animal models without interrupting Cisplatin’s therapeutic agency. Finally, more studies are required to validate the TUNE grading criteria to explore its utility as an ototoxicity grading criterion that can be universally used to communicate ototoxicity outcomes during Cisplatin chemotherapy.

The interaction between short oligodeoxynucleotides of specific sequence with cisplatin, cis-Pt(NH₃)₂Cl₂, has been examined under single stranded and duplexing conditions by ¹H nuclear magnetic resonance (NMR) spectroscopy. The oligonucleotides were synthesized by a modified phosphotriester technique adapting procedures initially used in oligoribonucleotide synthesis. The oligo sequences were designed to favour the intrastrand cis-Pt(NH₃)₂[d(-GpXₙpG-)-N7(l),N7(n+l)] crosslink, where X was up to three thymine units. Variable pH NMR was used to determine the site of platination on the oligomer. Variable temperature NMR was used to determine changes in base stacking and duplex formation resulting from oligomer platination. In the short oligomers, the intrastrand cisplatin crosslink formed between terminal guanines resulted in the internal section of the sequence being bulged out of a normal stacking orientation. The chemical shifts of the guanine H-8 resonances indicated that platination caused one of the guanine bases to flip from the normal anti geometry into a more syn-like orientation. This was observed for the three oligomers examined (X=thymidine, n=1,2,3). Variable temperature NMR of exchangeable imino protons in the oligomers with larger loops (n=2,3), indicated that the loop region of the complex was a random coil and that water access to the loop was restricted. i i i Longer sequences were examined which contained the cis-Pt(NH₃)₂[d(GpXₙpG)-] complex as well as external nucleotide units, 3' and 5' to the platinated region. Platination disrupted intrastrand base stacking of nucleotides externally adjacent to the platinum complex. Complementary and partially complementary sequences were examined under duplexing conditions. Stabilities, reflected in the Tₘ of the duplex, of fully complementary hexamer, heptamer and octamer oligomer mixtures were obtained by variable temperature NMR. Changes in duplex stability resulting from oligomer sequence and length along with the nature of the duplex to coil transition were discussed. Imperfect duplexes, designed to mimic the loop structures formed in platinated oligomers, indicated that the duplex containing one extra core thymine formed a helix resembling the fully complementary hexamer duplex with the extra base stacked out of the helix. With the core of the duplex containing two thymine units and one opposing complementary adenine, both thymines stacked into the helix with the adenine oscillating between the two thymines. When the oligomer mixture contained two extra thymine units with no opposing complements, duplex formation was not observed. A comparison between the duplex to coil transition in normal and imperfect duplexes was discussed. Similar duplex experiments were carried out using the platinated oligomer sequences. In each case examined, aggregation of the platinated strand, coupled with the oligomer sequences employed contributed to the failure of duplex formation. / Thesis / Doctor of Philosophy (PhD)

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

No description available.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references.

Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs due to its ability to effectively damage DNA and cause cell death. Despite this, cisplatin still suffers from two main drawbacks: toxicity and drug resistance. Many cisplatin-like compounds have been synthesized via traditional methods of drug design but very few have been able to enter clinical trials or even be approved for clinical use. The reason why so many compounds have been rejected is that their reaction mechanisms are rarely understood. By observing and studying the reaction mechanisms of a drug at the molecular level, the reaction can be optimized to enhance its therapeutic effects. The powerful technique of time-resolved pump-probe femtosecond laser spectroscopy was performed by Lu et al. to reveal the extremely high reactivity of cisplatin with weakly-bound electrons, thus providing a deeper understanding of this drug’s therapeutic effects. Taking advantage of this reaction mechanism, a molecular promoter can be identified to amplify the therapeutic efficacy of cisplatin by combination in a synergistic manner. Through cell survival rate measurements, fluorescence microscopic studies to view cell death, cell cycle analysis and DNA fragmentation measurements via flow cytometry, as well as absorption spectroscopic studies, the synergistic effects between cisplatin and a new molecular promoter (PM2A) were measured. This new chemotherapeutic regimen, which was designed based on the electron-transfer reaction mechanism of cisplatin, can be used to decrease the required doses of cisplatin used in the clinic (to effectively reduce its toxic side effects), to circumvent the drug resistance and to improve targeting to cancer cells.

A typical clinical cis-diamminedichloroplatinum (II) (cisplatin) dosing regimen consists of repeated cycles of five to seven daily low dose treatments followed by a one to two week recovery period. While effective, this dosing structure results in a prolonged, and sometimes permanent, infertility in men. Undifferentiated spermatogonia, including spermatogonial stem cells (SSCs), are theoretically capable of repopulating the seminiferous tubules after exposure has ceased. It is proposed that an altered spermatogonial environment during recovery from the initial treatment cycle may drive an increase in SSC mitotic cell activity, rendering the SSC pool increasingly susceptible to cisplatin-induced cell death from subsequent cycles. The undifferentiated spermatogonia population and niche of the adult mouse (C57/BL/6J) were examined during the recovery period of a clinically-relevant course of one and two cycles of 2.5 mg/kg/d of intraperitoneal cisplatin and were compared to mice receiving an equivalent cumulative dose in a single cycle (5.0 mg/kg/d) and vehicle treated controls. Histological examination of the testicular epithelium revealed an increase in the disorganization of spermatogenesis correlating with the number of exposure cycles. Quantification of TUNEL positive cells showed an increase in apoptotic germ cells early in the recovery period in mice exposed to cisplatin compared to control animals. Immunohistochemical (IHC) examination of Foxo1 (undifferentiated spermatogonia marker) showed an increase in the undifferentiated spermatogonia population late in the recovery period in mice exposed to one cycle of 2.5 mg/kg/d, but not following two cycles of 2.5 mg/kg/d. Analysis of BrdU incorporation after dosing indicated a decrease in mitotic activity of early germ cells immediately after cisplatin exposure followed by a return to basal levels by the conclusion of the initial recovery period. No such rebound was observed during the second recovery period. IHC investigation of glial cell line-derived neurotrophic factor (GDNF), a recognized SSC niche factor, revealed an increase in production along the basal Sertoli cell membrane throughout the recovery period in all treatment groups. Taken together, these data establish that the impact of cisplatin exposure on the functional stem cell pool and niche correlates with: (1) the number of dosing cycles; (2) mitotic activity of early germ cells; and (3) alterations in the basal Sertoli cell GDNF expression levels after cisplatin-induced testicular injury. / text

Cisplatin is one of the most widely used chemotherapeutic anti-cancer drugs due to its ability to effectively damage DNA and cause cell death. Despite this, cisplatin still suffers from two main drawbacks: toxicity and drug resistance. Many cisplatin-like compounds have been synthesized via traditional methods of drug design but very few have been able to enter clinical trials or even be approved for clinical use. The reason why so many compounds have been rejected is that their reaction mechanisms are rarely understood. By observing and studying the reaction mechanisms of a drug at the molecular level, the reaction can be optimized to enhance its therapeutic effects. The powerful technique of time-resolved pump-probe femtosecond laser spectroscopy was performed by Lu et al. to reveal the extremely high reactivity of cisplatin with weakly-bound electrons, thus providing a deeper understanding of this drug’s therapeutic effects. Taking advantage of this reaction mechanism, a molecular promoter can be identified to amplify the therapeutic efficacy of cisplatin by combination in a synergistic manner. Through cell survival rate measurements, fluorescence microscopic studies to view cell death, cell cycle analysis and DNA fragmentation measurements via flow cytometry, as well as absorption spectroscopic studies, the synergistic effects between cisplatin and a new molecular promoter (PM2A) were measured. This new chemotherapeutic regimen, which was designed based on the electron-transfer reaction mechanism of cisplatin, can be used to decrease the required doses of cisplatin used in the clinic (to effectively reduce its toxic side effects), to circumvent the drug resistance and to improve targeting to cancer cells.