A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine. / Patients diagnosed with Acute myeloid leukemia (AML) often become resistant to standard chemotherapeutic regimens. Cytarabine, a nucleoside analog, is the standard of care therapy for AML treatment. We hypothesized that by using an siRNA platform to inhibit 572 kinases in combination with Ara-C (cytarabine) in two AML cell lines (THP-1 and TF-1) we would be able to identify potential therapeutic targets to improve sensitivity to Ara-C (cytarabine). Our siRNA screen identified CHK1 as the most potent sensitizer to Ara-C. However, other kinases involved in DNA repair and checkpoint activation also improved sensitivity of cells to Ara-C. Checkpoints are present at the G1/S transition, within S phase and at the G2/M transition. Within the G2/M checkpoint, CHK1 functions to halt the transition to mitosis when DNA damage is detected. Additional siRNA screening of proteins that function in the G2/M checkpoint identified WEE1 as a potent sensitizer as well. It is hypothesized that abrogation of the G2/M checkpoint prevents repair pathways from repairing genotoxic damage caused by chemotherapeutics. Therefore, a literature review of the checkpoint targeting and rational therapeutic targets for future treatments was conducted. Both WEE1 and CHK1 are currently 4 being targeted in order to enhance activity of various genotoxic chemotherapeutics in many different cancers and present rational targets for further investigated in combination with Ara-C in AML.

Thesis (M.S.)--University of Wisconsin--Madison. / Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 37-49).

Thesis (Ph. D.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 162-175).

Translation of thesis, Copenhagen.

Thesis (M.D.)—Boston University

The chloroleukemia (chloroma) in the Cancer Research Centre, U.B.C. could be transplanted into adult Sprague-Dawley rats with tumour homogenates, whole blood and ascitic fluid containing intact cells. Cell-free filtrates of the ascitic fluid did not give rise to tumours. It was considered probable that intact cells were required for the transmission of this leukemia. The present study showed that there was a 'latent period' of 10 to 12 days after which the chloroma grew rapidly until the death of the animal (ca 27 days). The tumour contained substantial amounts of free protoporphyrin and had high myeloperoxidase activity. The protoporphyrin concentration increased markedly and continuously with the age of the tumour but its rate of synthesis (from glycine-2-C¹⁴) declined after the 19th day, i.e..protoporphyrin accumulated in the tumour. The myeloperoxidase activity increased between the 13th and 15th day after transplantation and thereafter fell sharply. The effect of two drugs - Vinblastine (VLB) and 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC) on certain aspects of the biosynthetic activity of this particular adult chloroma was investigated. VLB inhibited the incorporation of glycine-2-C¹⁴ into both RNA and protein earlier and to a greater extent than into the DNA and protoporphyrin. This tumour, although of hematopoietic origin, did not therefore show the high sensitivity of normal bone marrow to VLB. DDC markedly increased the Δ -aminolevulinic acid synthetase activity and protoporphyrin concentration in the liver of rats but had no effect on the tumour protoporphyrin synthesis although there was more than a 20-fold increase in Δ -aminolevulinic acid synthetase activity. It was suggested therefore that the enzyme Δ-aminolevulinic acid synthetase may be rate-limiting in the liver but not in the tumour. In the course of the present work, an improved method for the separation of porphyrin esters based on partition chromatography on alumina was developed. / Medicine, Faculty of / Biochemistry and Molecular Biology, Department of / Graduate

Thesis (M. Med. Sc.)--University of Queensland, 2001. / Includes bibliographical references.

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Thesis (M. Med. Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 36-41).

Thesis (M.Med.Sc.)--University of Hong Kong, 2000. / Includes bibliographical references (leaves 36-41). Also available in print.