According to U.S. Breast Cancer Statistics, about 1 in 8 U.S. women will develop invasive breast cancer during their lifetime. Chemotherapeutics that are used on patients currently often lead to tumor resistance, bone marrow suppression and cachexia. This study evaluated a novel combination of three non-mutagenic compounds for their effectiveness against mammary tumor cells, toxicity towards immune cells, ability to provoke the expression of immunogenic cell death (ICD) markers, and killing in 3D tumor models. Methotrexate (MTX), 2-deoxyglucose (2DG), and wogonin (WGN) were combined at doses well below their EC50 values yet effectively killed human and mouse breast cancer cells. The combination inhibited cancer cell colony formation and induced a high degree of cell death in multiple malignant tumor cell lines. Importantly, the combination did not significantly inhibit the viability of peripheral-blood mononuclear cells (PBMCs), even when employed at 3X the concentration that killed cancer cells. In marked contrast, low-dose doxorubicin, a common therapeutic for breast cancers, significantly decreased PBMC viability and increased the percentage of cell death. Our novel combinatorial therapy (Trifecta) elicited the significant expression of three ICD hallmarks: calreticulin surface expression, ATP secretion, and HMGB-1 release. In all cases, Trifecta elicited an equal or greater degree of ICD-marker expression compared to doxorubicin, a known inducer of ICD. We show significant efficacy of Trifecta against human and mouse mammary 3D tumor models grown in Matrigel® ECM-complex containing culture medium, and reaffirm the marked resistance of tumorspheres towards the conventional chemotherapeutic doxorubicin. The effectiveness of Trifecta in an acceptable surrogate model for mouse studies bodes well for translation of our findings to the clinic. In conclusion, Trifecta has proven highly effective against tumor cells grown either as monolayers or tumorspheres, without significant cytotoxic effects towards proliferating immune cells. Furthermore, treatment with this combination elicits ICD, which has the potential to prime an adaptive immune response against tumor cells and prevent future relapse. The drugs chosen for our combination target metabolic pathways that cancer cells are heavily dependent upon and do not interact with or induce mutations in DNA. These properties place Trifecta at the forefront of developing anticancer therapies. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2020. / FAU Electronic Theses and Dissertations Collection

No description available.

Methotrexate (MTX) is an antimetabolite anticancer agent that is used in treatment of multiple cancers, such as acute lymphoblastic leukaemia and osteosarcoma. A lack of selective tumour toxicity is one of the major problems associated with MTX chemotherapy, especially when given at high doses, as in high dose MTX (HDMTX) therapy. MTX causes various toxicity problems including life-threatening nephrotoxicity, haematological toxicity and neurotoxicity. Overcoming this toxicity is of great importance and has been attempted in various ways, not least via the design of prodrugs. The concept of tumour protease, and specifically matrix metalloproteinase (MMP), activated prodrugs was the focus of the work described in this thesis. This concept relies upon attachment of an MMP-sensitive peptide sequence to a specific site in a drug structure, so as to inactive it. The activity of the parent drug is restored once it is activated by the MMPs in the tumour microenvironment. In this work, different MMP-sensitive peptide sequences linked to MTX were synthesised, resulting in 63 MTX prodrugs. The MMP-mediated activation of these conjugates in tumour tissues (specifically HT1080 homogenates) ex vivo was assessed and the results were compared to the activation of these conjugates in various normal tissues specifically liver, kidney and lung. Specific criteria were established for the selection of promising conjugates for more detailed study. From 7 promising compounds, compound 75 was identified as the lead prodrug, demonstrating selective MMP activation, as indicated by inhibition of its activation by broad spectrum MMP inhibitor ilomastat. The pharmacokinetics of compound 75 was studied in tumour (HT1080) xenograft-bearing mice and the results were compared to those obtained from administration of equimolar doses of conventional MTX. Compound 75 led to enhanced tumour concentrations of MTX, with reduced exposure to normal tissues in vivo compared to conventional MTX therapy. Furthermore, the efficacy of equimolar doses of compound 75 and directly dosed MTX in reduction of HT1080 volume were compared. Superior antitumour activity was observed with compound 75 compared to MTX treatment. Compound 75 is the first example of an MMP-activated prodrug to be reported with enhanced therapeutic index, as evidenced by a full in vivo pharmacokinetic analysis and normal tissue metabolism data. The data presented in thesis support the concept of MMP-activated prodrug development, and form a strong foundation upon which to develop a clinicallyuseful MTX prodrug, with the potential to enhance efficacy and reduce toxicity to the patient.

Bibliography: leaves 186-211.

Methotrexate (MTX) is an antimetabolite anticancer agent that is used in treatment of multiple cancers, such as acute lymphoblastic leukaemia and osteosarcoma. A lack of selective tumour toxicity is one of the major problems associated with MTX chemotherapy, especially when given at high doses, as in high dose MTX (HDMTX) therapy. MTX causes various toxicity problems including life-threatening nephrotoxicity, haematological toxicity and neurotoxicity. Overcoming this toxicity is of great importance and has been attempted in various ways, not least via the design of prodrugs. The concept of tumour protease, and specifically matrix metalloproteinase (MMP), activated prodrugs was the focus of the work described in this thesis. This concept relies upon attachment of an MMP-sensitive peptide sequence to a specific site in a drug structure, so as to inactive it. The activity of the parent drug is restored once it is activated by the MMPs in the tumour microenvironment. In this work, different MMP-sensitive peptide sequences linked to MTX were synthesised, resulting in 63 MTX prodrugs. The MMP-mediated activation of these conjugates in tumour tissues (specifically HT1080 homogenates) ex vivo was assessed and the results were compared to the activation of these conjugates in various normal tissues specifically liver, kidney and lung. Specific criteria were established for the selection of promising conjugates for more detailed study. From 7 promising compounds, compound 75 was identified as the lead prodrug, demonstrating selective MMP activation, as indicated by inhibition of its activation by broad spectrum MMP inhibitor ilomastat. The pharmacokinetics of compound 75 was studied in tumour (HT1080) xenograft-bearing mice and the results were compared to those obtained from administration of equimolar doses of conventional MTX. Compound 75 led to enhanced tumour concentrations of MTX, with reduced exposure to normal tissues in vivo compared to conventional MTX therapy. Furthermore, the efficacy of equimolar doses of compound 75 and directly dosed MTX in reduction of HT1080 volume were compared. Superior antitumour activity was observed with compound 75 compared to MTX treatment. Compound 75 is the first example of an MMP-activated prodrug to be reported with enhanced therapeutic index, as evidenced by a full in vivo pharmacokinetic analysis and normal tissue metabolism data. The data presented in thesis support the concept of MMP-activated prodrug development, and form a strong foundation upon which to develop a clinically-useful MTX prodrug, with the potential to enhance efficacy and reduce toxicity to the patient. / Libyan government / The full text will be available after the extended embargo: 5th March 2027

No description available.

The two options for treatment of the inflammatory bowel disease Crohn’s Disease are surgery and pharmacotherapy. Pharmacotherapy with the goal of inducing and maintaining remission is the preferred treatment route, but the current medications are not entirely effective in achieving these goals. Approximately half of Crohn’s Disease patients will be required to have surgical bowel resection within 20 years of diagnosis, and many patients are at higher risk of adverse events such as cancer, either directly as a result of Crohn’s Disease or due to side-effects of the drugs used to treat the condition. Medical management of the disease is very complicated and there is a relative lack of uniformity in treatment. Different drugs used either in monotherapy, sequential therapy, or combination therapy produce differing levels of efficacy and different outcomes. This analysis provides an overview of the four major classes of drugs used in the treatment of Crohn’s Disease and a discussion of the overall efficacy of the different methods of treatment. While more studies need to be conducted into the differing outcomes of monotherapy, sequential therapy, and combination therapy, it appears as though any treatment involving the use of biologics such as tumor necrosis factor alpha (TNF-alpha) inhibitors results in improved outcomes relative to treatment styles that lack the use of biologics.

Fármacos antiproliferativos vêm sendo utilizados em procedimentos de angioplastia, onde são administrados localmente por meio de \"stents\" farmacológicos. Embora seja possível que um tratamento sistêmico apresente maior eficiência, os efeitos colaterais dos fármacos antiproliferativos disponíveis constituem uma grande limitação. Estudos recentes em nosso laboratório demonstraram que uma nanoemulsão lipídica rica em colesterol concentra-se em regiões onde a proliferação celular é maior, possivelmente devido a uma maior demanda por colesterol para a síntese de membranas celulares. Assim, consideramos a possibilidade de utilização desta nanoemulsão como veículo de fármacos antiproliferativos para o tratamento da aterosclerose. No presente trabalho, dezesseis coelhos brancos, machos, da raça New Zealand, pesando aproximadamente 3 kg, foram submetidos a uma dieta contendo 1% de colesterol durante quatro semanas e divididos em dois grupos: um grupo recebendo uma injeção endovenosa contendo apenas solução salina e outro grupo tratado com uma associação de etoposídeo e metotrexato, veiculados na nanoemulsão lipídica. A análise da morfometria macroscópica mostra que o tratamento reduz as áreas de lesão aterosclerótica em aproximadamente 84% (razão da área de lesão sobre área total 0,57±0,2 nos animais controle versus 0,089±0,05 nos animais tratados, p<0,05). Houve redução de aproximadamente 3 vezes na razão da íntima-média dos animais tratados em relação aos animais controle. Adicionalmente, observamos que o tratamento reduz a migração de macrófagos na camada íntima do arco aórtico destes animais. Houve amplificação do efeito terapêutico em função da associação destes fármacos e redução na toxicidade. Portanto, a associação destes fármacos antiproliferativos veiculados em um sistema nanoparticulado pode ser promissora para o tratamento da aterosclerose. Estudos em humanos deverão confirmar o potencial desta proposta na terapêutica cardiovascular. / Drug eluting stents have been used in angioplastic procedures to deliver antiproliferative drugs directly to arterial tissue. Presumably, a systemic treatment could be more effective than local administration, but the side-effects of available antiproliferative drugs limit this approach. In recent studies, we have shown that a cholesterol-rich nanoemulsion concentrates in sites of high cell proliferation, possibly due to a high demand of cholesterol to membrane cell synthesis. Thus, we sought to test the emerging hypothesis that our nanoemulsion could be used as a vehicle to antiproliferative drugs for systemic treatment of atherosclerosis. In the present study, sixteen New Zealand White rabbits weighing from 3.2 to 3.8 kg were submitted to a diet containing 1% cholesterol during 4 weeks and then they were split in two groups: a group treated with an intravenous injection of saline solution and a group treated with an association of etoposide and methotrexate delivered in our lipid nanoemulsion. We have shown by macroscopic morphometry that the treatment reduced the lesion areas by roughly 84% (lesion area/total area ratio 0,57±0,2 in control animals, versus 0,089±0,05 in treated animals, p<0,05). The intima-media ratio was reduced by three fold in treated animals. Furthermore, we have observed a reduction in macrophage migration to the arterial intima. The association of etoposide and methotrexate resulted in a synergistic effect without increasing the toxicity. In conclusion, the association of antiproliferative drugs delivered in a nanoemulsion is a promising approach for atherosclerosis treatment. Further studies in humans are needed to confirm the potential of this treatment in cardiovascular therapeutics.

by Wing-yu Tang. / Bibliography: leaves 129-138 / Thesis (M.Ph.)--Chinese University of Hong Kong, 1985

No description available.