<p>Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect.</p><p>Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases.</p><p>Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases.</p><p>In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.</p>

Standard dosing of chemotherapy based on body surface area (BSA) results in large individual differences in toxicity due to a large inter-patient variability in pharmacokinetics (PK) and pharmacodynamics (PD). This results in under-dosing in certain patients with a potentially weaker antitumoral effect. Three clinical studies of individually tailored dosing of chemotherapy, based on haematological toxicity were conducted. In the first study, 26 women with metastatic breast cancer were treated with tailored and dose-escalated 5-fluorouracil, epirubicin and cyclophosphamide, supported by G-CSF (dFEC). In the second study 525 patients with high-risk primary breast cancer were randomised between dFEC and high-dose chemotherapy with autologous bone-marrow transplantation. The feasibility of a FEC regimen with doubled cyclophosphamide dose to mobilise peripheral stem cells was investigated. In the third study, 44 metastatic patients were treated with tailored epirubicin and docetaxel (ET). PK and PD were also investigated in these patients. The potential effects of G-CSF on MRI tumour evaluation were studied in 18 patients with skeletal metastases. Toxicity-based dosing entailed an evenly distributed two- to three-fold range of tolerated doses in all three studies. Efficacy and toxicity were not correlated to tolerated dose-levels. Tailored dFEC resulted in a response rate of 81% and the same regimen resulted in fewer breast cancer relapses compared with standard FEC followed by high-dose therapy. Toxicity was manageable except for an increased rate of secondary leukaemia. The modified FEC could safely mobilise sufficient numbers of stem-cells. Tailored ET resulted in a response rate of 63%. The inter-individual variability in drug clearance was larger than the inter-occasion variability and a semi-physiological model of PK and PD could predict leukocyte nadir and duration. An increased diffuse MR signal in the long TE IR-TSE sequence was observed in normal bone-marrow during G-CSF treatment; this could be mistaken as disseminated metastatic disease and could obscure focal metastases. In conclusion, the concept of individually tailored toxicity-based dosage of chemotherapy was equally feasible in primary and metastatic breast cancer, in two different chemotherapy regimens and in treatment with or without G-CSF support and may provide a pragmatic way of overcoming the shortcomings of standard BSA-based dosing.

Allergic asthma is an immunological disease, mediated by CD4+ Th2 cells, and its prevalence has increased over recent decades. Features of allergic asthma include airway hyperresponsiveness (AHR), airway eosinophilia, excessive airway mucus production, and increased IgE and Th2 cytokine levels. Airway remodeling with pulmonary fibrosis is noted in the progress of asthma. In this thesis, a murine model of allergic asthma was used to investigate the effect of cyclophosphamide (CY) on asthma and the involvement of regulatory T cells (Treg), and the role of Granulocyte-macrophage colony stimulating-factor (GM-CSF) in allergic asthma by using GM-CSF knockout mice. CY is a cytotoxic agent, which paradoxically augments several immune responses. The first part of this thesis was aimed to study the effects of CY in a murine model of allergic airway inflammation. BALB/c mice were immunized with ovalbumin (OVA) on days 0 and 14, and challenged with aerosolized OVA from days 21 to 27. Some mice additionally received CY on days -2 and 12. In the CY-treated animals, pronounced worsening of inflammatory features was noted, including increases in eosinophil infiltration, epithelial thickness, mucus occlusion and eosinophil numbers in bronchoalveolar lavage fluid (BALF). Increased total and OVA-specific serum IgE were also noted in the CY-treated animals. In cell cultures from peritracheal lymph nodes, the Th2 cytokines IL-4 and IL-5 were elevated in animals treated with CY. It was hypothesized that the effects of CY could be caused by reduced immunosuppression mediated by Treg. mRNA expression of the immunosuppressive cytokines IL-10 and TGF-beta was reduced in the lungs of CY-treated mice. The expression of FoxP3, a marker of naturally occurring Treg, was significantly reduced in spleens, thymuses and peritracheal lymph nodes after the second injection of CY, and in the lung tissue after allergen challenge in CY-treated mice. Furthermore, lung IL-10-producing CD4+ T cells and CTLA-4+-bearing CD4+ T cells were reduced after allergen aerosol challenge in CY-treated mice. Thus CY worsened the features of allergic pulmonary inflammation in this model, in association with increased production of IgE and Th2 cytokines. The reduction in expression of FoxP3 and immunosuppressive cytokines by CY suggests that toxicity to Treg may contribute to the increased inflammation. GM-CSF plays a role in the growth, development, and maturation of bone marrow hemopoietic cells into mature blood cells, and has been proposed to be involved in potentiating the function of inflammatory cells in allergic inflammation. In the second part of this thesis, GM-CSF knockout (KO) mice were used to investigate the role of GM-CSF. In allergic KO mice, airway eosinophils were only shown in the perivascular, but not peribronchial areas in the lung, compared to the allergic wild-type (WT) mice in which eosinophil infiltration appeared in both areas. Eosinophil numbers were drastically reduced in the bronchoalveolar lavage fluid (BALF) of KO mice. IL-5 production in the lung tissue and BALF in allergic KO mice was reduced; similar results were also found in peritracheal draining lymph nodes after in vitro stimulation assays. However, IL-4 and IL-13 production, airway hyperresponsiveness (AHR), and serum IgE production were not affected in allergic KO mice. Surprisingly, lung IFN-gamma mRNA and BALF levels were increased in allergic KO mice. Lung mRNA levels of CCR3, a key chemokine receptor on eosinophils, were significantly reduced in allergic KO mice, whereas expression of the chemokines eotaxin and RANTES were at similar levels in allergic KO and WT mice. Lung mRNA levels of the IFN-gamma-inducible chemokines Mig (CXCL9) and IP-10 (CXCL10), which are antagonists of CCR3, and their receptor CXCR3 were increased in allergic KO mice, compared with allergic WT mice. Data obtained from flow cytometry showed more eosinophils survived in the lung of WT mice than KO mice. Another allergy model, a peritoneal allergy model was performed to investigate inflammation in a different model. Leukocyte subpopulations such as neutrophils, eosinophils, macrophages, and lymphocytes were reduced in the peritoneal lavage fluid of allergic KO mice. The findings revealed that GM-CSF is essential for IL-5 production, pulmonary airway eosinophilia and eosinophil survival. In the absence of GM-CSF, over-production of IFN-???? may induce chemokines, including Mig and IP-10, which are antagonists for CCR3 and may reduce airway eosinophil infiltration. In this thesis, a murine model of allergic asthma has been used to obtain novel findings on the regulation of allergic inflammation. The results with CY are relevant to the treatment of asthma patients with CY and other cytotoxic agents. The findings in the GM-CSF KO mice suggest that GM-CSF is a potential therapeutic target in asthma, and that in assessment of new therapeutic agents for asthma, effects on GM-CSF should be considered.

Brain stem remyelination following demyelination induced by ethidium bromide (EB) is carried out by oligodendrocytes and Schwann cells that invade the central nervous system when astrocytes are lost. Although oligodendrocyte remyelination is detected from 13 days onward within the lesions, the origin of the remyelinating cells is not known. To clarify oligodendrocyte origin as well as to observe astrocytic behaviour in normal (n=22) as well as immunosuppressed animals (n=22) adult Wistar rats were injected with EB in the basal cisterna. Wistar rats had an EB injection while treated with cyclophosphamide (astrocyte investigation, n=12) or cyclosporine A (oligodendrocyte study, n=10). Control animals had a single injection of 10 μl of 0.9% saline (n=16). For the investigation on astrocytes, the rats were killed at 1, 2, 3, 7, 14 and 21 days a.i. GFAP labelled astrocytes were conspicuous within the lesions and isomorphic gliosis was detected, more marked in those rats immunosuppressed with CY. Nonetheless a significant difference among the groups could not be established because of the mean deviations detected by the image studies. For the oligodendrocyte investigation the rats were killed at 15, 21 and 31 days a.i. Lesions of EB injected in normal and cyclosporine A-treated Wistar rats labelled positive for OSP (oligodendrocytes specific protein). This result points to mature oligodendrocytes as a source of remyelinating cells to restore the lost myelin sheaths after EB injection. The EB model of demyelination allowed the observation of the neuroglia in lesions where remyelination is made up by mature cells of the oligodendroglial lineage and where astrocytes respond selectively to immunosuppressive drugs that modify the inflammatory reaction induced by EB / Remielinização após desmielinização com brometo de etídio (BE) no tronco encefálico de ratos é realizada por oligodendrócitos e células de Schwann que invadem o tecido após a morte dos astrócitos. Embora a remielinização por oligodendrócitos seja detectada a partir dos 13 dias pós-intoxicação, a origem das células remielinizantes não é conhecida. Para esclarecer essa origem bem como o comportamento astrocitário em lesões induzidas pelo BE em ratos adultos normais (n=22) ou sob terapia imunomoduladora (n=22), ratos Wistar adultos receberam uma injeção de 10 μl de BE na cisterna basal. Ratos Wistar receberam a injeção de BE enquanto sob terapia imunossupressora com ciclofosfamida (estudo astrocitário) (n=12) ou ciclosporina-A (n=10) (estudo da oligodendróglia). Os animais controle receberam uma injeção de 10 μl 0.9% de solução salina (n=16). Para o estudo astrocitário, os animais foram sacrificados aos 1, 2, 3, 7, 14 e 21 dias pós-injeção de BE. Astrócitos foram marcados com GFAP (proteína glial fibrilar ácida) e foi detectada gliose isomórfica nas lesões, mais marcada naqueles animais tratados com ciclofosfamida (CY). Embora existisse diferença entre a marcação por GFAP nos ratos que receberam somente BE e os que receberam BE e CY, os desvios das médias obtidas através da análise de imagem, não permitiram uma conclusão sobre a significância dessa diferença. Os ratos do experimento sobre a oligodendróglia foram sacrificados aos 15, 21 e 31 dias p.i. do BE. Tecidos de ratos normais injetados com BE e ratos injetados e tratados com ciclosporina foram marcados com imunofluorescência (IF) para OSP (proteína específica do oligodendrócito) que marca células maduras da linhagem oligodendroglial. O resultado foi a marcação de células maduras que remielinizavam em áreas próximas ao tecido normal, mostrando oligodendrócitos maduros como fonte celular na reparação das bainhas perdidas. O modelo de desmielinização do BE permitiu estudar a atividade da neuróglia em lesões que foram remielinizadas por oligodendrócitos maduros e nas que os astrócitos responderam seletivamente a imunossupressores que interferem com a reação inflamatória dentro do tecido

Objetivo: avaliar marcadores de reserva ovariana e a presença de anticorpo anti-corpo lúteo (anti-CoL) em pacientes com lúpus eritematoso sistêmico (LES) de início na infância. Métodos: A presença do anti-CoL foi avaliada através de immunoblot em cinquenta e sete mulheres com LES e 21 controles saudáveis. A reserva ovariana foi estimada através das dosagens do hormônio folículo estimulante (FSH), hormônio luteinizante (LH), estradiol, hormônio anti- Mülleriano (AMH) e da contagem de folículos antrais (CFA). Foram também avaliados dados demográficos, alterações menstruais, atividade da doença, dano cumulativo e tratamento. Resultados: a mediana da idade atual foi similar nos pacientes com LES em relação aos controles (27,7 vs. 27,7 anos, p=0,414). A mediana do AMH (1,1 vs. 1,5ng/mL, p=0,037) da CFA (6 vs. 16 p<0,001) forma significantemente menores nos pacientes com LES quando comparados aos controles, porém sem alterações menstruais significantes. A presença do anti-CoL foi observada apenas nos pacientes com LES (16% vs. 0%, p=0,103) e não foi relacionada com dados demográficos, parâmetros de reserva ovariana, atividade da doença, dano cumulativo ou tratamento. Avaliação dos pacientes tratados com ciclofosfamida mostrou níveis elevados de FSH quando comparados com os pacientes que não receberam ciclofosfamida e com controles (8,8 vs. 5,7 vs. 5,6IU/L, p=0,032) e níveis menores de AMH e CFA (0,4 vs. 1,5 vs. 1,5ng/mL, p=0,004; 4,0 vs. 6,5 vs. 16IU/L, p=0,001; respectivamente). Dezenove pacientes foram tratados com metotrexate sem histórico de uso de ciclofosfamida sendo evidenciada uma correlação negativa entre a dose cumulativa de metotrexate e os níveis de AMH (p=0,027, r=-0,507). Conclusões: este estudo identificou que altas doses ciclofosfamida e metotrexato são causas relevantes de disfunção ovariana subclínica durante a idade reprodutiva em mulheres com LES de início na infância / Objective: To assess ovarian reserve markers and anti-corpus luteum antibodies (anti-CoL) in systemic lupus erythematosus (SLE) patients with onset before adulthood. Methods: Fifty-seven SLE female patients and 21 healthy controls were evaluated for anti-CoL by immunoblot. Ovarian reserve was assessed by: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti-Müllerian hormone (AMH) and antral follicle count (AFC). Demographic data, menstrual abnormalities, disease activity, damage and treatment were also analyzed. Results: The median of current age was similar in SLE patients and controls (27.7. vs. 27.7 years, p=0.414). The median of AMH (1.1 vs. 1.5ng/mL, p=0.037) and AFC (6 vs. 16, p<0.001) were significantly reduced in SLE patients versus controls without significant menstrual abnormalities. Anti-CoL was solely observed in SLE patients (16% vs. 0%, p=0.103) and not associated with demographic data, ovarian reserve parameters, disease activity/damage and treatment. Further evaluation of patients treated with cyclophosphamide revealed a higher median of FSH levels compared to SLE patients not treated with cyclophosphamide and controls (8.8 vs. 5.7 vs. 5.6IU/L, p=0.032) and a lower median AMH levels and AFC (0.4 vs. 1.5 vs. 1.5ng/mL, p=0.004; 4.0 vs. 6.5 vs. 16IU/L, p=0.001; respectively). Nineteen patients were treated with methotrexate without cyclophosphamide use, and a negative correlation was observed between cumulative methotrexate dose and AMH levels (p=0.027, r=-0.507). Conclusions: The present study identifies high doses of cyclophosphamide and methotrexate as relevant causes of subclinical ovarian dysfunction during reproductive ages in SLE patients with onset before adulthood

Objetivo: avaliar marcadores de reserva ovariana e a presença de anticorpo anti-corpo lúteo (anti-CoL) em pacientes com lúpus eritematoso sistêmico (LES) de início na infância. Métodos: A presença do anti-CoL foi avaliada através de immunoblot em cinquenta e sete mulheres com LES e 21 controles saudáveis. A reserva ovariana foi estimada através das dosagens do hormônio folículo estimulante (FSH), hormônio luteinizante (LH), estradiol, hormônio anti- Mülleriano (AMH) e da contagem de folículos antrais (CFA). Foram também avaliados dados demográficos, alterações menstruais, atividade da doença, dano cumulativo e tratamento. Resultados: a mediana da idade atual foi similar nos pacientes com LES em relação aos controles (27,7 vs. 27,7 anos, p=0,414). A mediana do AMH (1,1 vs. 1,5ng/mL, p=0,037) da CFA (6 vs. 16 p<0,001) forma significantemente menores nos pacientes com LES quando comparados aos controles, porém sem alterações menstruais significantes. A presença do anti-CoL foi observada apenas nos pacientes com LES (16% vs. 0%, p=0,103) e não foi relacionada com dados demográficos, parâmetros de reserva ovariana, atividade da doença, dano cumulativo ou tratamento. Avaliação dos pacientes tratados com ciclofosfamida mostrou níveis elevados de FSH quando comparados com os pacientes que não receberam ciclofosfamida e com controles (8,8 vs. 5,7 vs. 5,6IU/L, p=0,032) e níveis menores de AMH e CFA (0,4 vs. 1,5 vs. 1,5ng/mL, p=0,004; 4,0 vs. 6,5 vs. 16IU/L, p=0,001; respectivamente). Dezenove pacientes foram tratados com metotrexate sem histórico de uso de ciclofosfamida sendo evidenciada uma correlação negativa entre a dose cumulativa de metotrexate e os níveis de AMH (p=0,027, r=-0,507). Conclusões: este estudo identificou que altas doses ciclofosfamida e metotrexato são causas relevantes de disfunção ovariana subclínica durante a idade reprodutiva em mulheres com LES de início na infância / Objective: To assess ovarian reserve markers and anti-corpus luteum antibodies (anti-CoL) in systemic lupus erythematosus (SLE) patients with onset before adulthood. Methods: Fifty-seven SLE female patients and 21 healthy controls were evaluated for anti-CoL by immunoblot. Ovarian reserve was assessed by: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti-Müllerian hormone (AMH) and antral follicle count (AFC). Demographic data, menstrual abnormalities, disease activity, damage and treatment were also analyzed. Results: The median of current age was similar in SLE patients and controls (27.7. vs. 27.7 years, p=0.414). The median of AMH (1.1 vs. 1.5ng/mL, p=0.037) and AFC (6 vs. 16, p<0.001) were significantly reduced in SLE patients versus controls without significant menstrual abnormalities. Anti-CoL was solely observed in SLE patients (16% vs. 0%, p=0.103) and not associated with demographic data, ovarian reserve parameters, disease activity/damage and treatment. Further evaluation of patients treated with cyclophosphamide revealed a higher median of FSH levels compared to SLE patients not treated with cyclophosphamide and controls (8.8 vs. 5.7 vs. 5.6IU/L, p=0.032) and a lower median AMH levels and AFC (0.4 vs. 1.5 vs. 1.5ng/mL, p=0.004; 4.0 vs. 6.5 vs. 16IU/L, p=0.001; respectively). Nineteen patients were treated with methotrexate without cyclophosphamide use, and a negative correlation was observed between cumulative methotrexate dose and AMH levels (p=0.027, r=-0.507). Conclusions: The present study identifies high doses of cyclophosphamide and methotrexate as relevant causes of subclinical ovarian dysfunction during reproductive ages in SLE patients with onset before adulthood

Vestibular evoked myogenic potentials (VEMPs) are short-latency electromyograms evoked by high-level acoustic stimuli recorded from surface electrodes over the tonically contracted sternocleidomastoid (SCM) muscle. These responses are presumed to originate in the saccule. The purpose of this preliminary report is to provide an overview of our initial experience with the VEMP by describing the responses obtained in five subjects. Click-evoked VEMPs were present at short latencies in two normal-hearing subjects, one patient with profound congenital sensorineural hearing loss, and one patient with a severe sensorineural hearing loss due to Meniere's disease. Additionally, VEMPs were absent in a patient with profound sensorineural hearing loss following removal of a cerebellopontine angle tumor. The amplitude of the VEMP was influenced by the amount of background activity of the SCM muscle, stimulus level, and stimulus frequency. Tone-burst evoked responses showed an inverse relationship between stimulus frequency and response latency. VEMPs may prove to be a reliable technique in the clinical assessment of vestibular function.

Les thérapies anticancéreuses ont connu ces dernières années un développement important ayant pour conséquence une amélioration dans la qualité de vie des patients. Cependant la survenue de résistances et la part significative de cancer sans traitement efficace nous oblige à envisager le développement de nouvelles stratégies anticancéreuses. Nous avons développé une nouvelle technique basée sur le principe du gène suicide en utilisant le gène du cytochrome P450 2B6 associé au cyclophosphamide (CPA). Cette technique qui consiste au transfert d'un gène métabolisant une prodrogue anticancéreuse dans la tumeur permet une sensibilisation des tumeurs à cette prodrogue. Le premier objectif de ce travail a consisté à améliorer le métabolisme de la prodrogue en construisant un gène muté du CYP2B6 en fusion avec la réductase, partenaire indispensable du CYP. Dans un deuxième temps nous avons transféré le gène CYP2B6TM-RED dans des cellules tumorales qui sont devenues sensibles au CPA entrainant une éradication des tumeurs. Ces résultats ont été confirmés in vivo sur des modèles de souris immunocompétentes. Nous avons, en plus de l'effet cytotoxique, mis en évidence un important effet bystander et le développement d'une immunité antitumorale spécifique. Ceci nous laisse penser que cette méthode peut permettre de protéger contre les récidives et les métastases. Les bons résultats obtenus dans le développement de cette nouvelle stratégie anticancéreuse, nous laissent espérer d'un futur passage en clinique. Pour cela de nouveaux modèles animaux devront être mis au point pour optimiser le transfert du transgène dans les tumeurs.

The aim of this work was to gain new knowledge about mechanisms of autoimmune uveitis and to test new therapeutic possibilities that have not yet been studied in uveitis or whose effect is questionable. The main emphasis was placed on the role of microorganisms in the process of uveitis. A mouse model of experimental autoimmune uveitis including a germ-free model was used to achieve the aims and samples of patients' intraocular fluids were analyzed. In the experimental model, the intensity of inflammation was evaluated in vivo clinically and post mortem histologically. The effect of immunomodulatory treatment was evaluated. The intensity of inflammation was compared between groups of germ-free and conventional mice. The therapeutic effect of antibiotics administered to affect microbiome was investigated in conventional mice. In intraocular fluid samples of patients with autoimmune uveitis signs of infection were monitored and levels of cytokines and other factors were evaluated. Evaluation of the effect of immunomodulatory therapy has demonstrated the efficacy of mycophenolate mofetil, which supports its wider use in the treatment of autoimmune posterior uveitis in human medicine. The decrease in bacterial load has led to a decrease in the intensity of inflammation, thereby confirming the importance of...

Indiana University-Purdue University Indianapolis (IUPUI) / ALDH isoenzymes are known to impact the sensitivity of certain neoplastic cells toward cyclophosphamides and its analogs. Despite its bone marrow toxicity, cyclophos-phamide is still used to treat various recalcitrant forms of cancer. When activated, cyclo-phosphamide forms aldophosphamide that can spontaneously form the toxic phospho-ramide mustard, an alkylating agent unless detoxified by ALDH isozymes to the carbox-yphosphamide metabolite. Prior work has demonstrated that the ALDH1A1 and ALDH3A1 isoenzymes can convert aldophosphamide to carboxyphosphamide. This has also been verified by over expression and siRNA knockdown studies. Selective small molecule inhibitors for these ALDH isoenzymes are not currently available. We hypothe-sized that novel and selective small molecule inhibitors of ALDH3A1 would enhance cancer cells’ sensitivity toward cyclophosphamide. If successful, this approach can widen the therapeutic treatment window for cyclophosphamides; permitting lower effective dos-ing regimens with reduced toxicity. An esterase based absorbance assay was optimized in a high throughput setting and 101, 000 compounds were screened and two new selective inhibitors for ALDH3A1, which have IC50 values of 0.2 µM (CB7) and 16 µM (CB29) were discovered. These two compounds compete for aldehyde binding, which was vali-dated both by kinetic and crystallographic studies. Structure activity relationship dataset has helped us determine the basis of potency and selectivity of these compounds towards ALDH3A1 activity. Our data is further supported by mafosfamide (an analog of cyclo-phosphamide) chemosensitivity data, performed on lung adenocarcinoma (A549) and gli-oblastoma (SF767) cell lines. Overall, I have identified two compounds, which inhibit ALDH3A1’s dehydrogenase activity selectively and increases sensitization of ALDH3A1 positive cells to aldophosphamide and its analogs. This may have the potential in improving chemotherapeutic efficacy of cyclophosphamide as well as to help us understand better the role of ALDH3A1 in cells. Future work will focus on testing these compounds on other cancer cell lines that involve ALDH3A1 expression as a mode of chemoresistance.