This agent was found to have broad-spectrum activity against a range of solid tumors and, to this day, remains the cornerstone for the treatment of colorectal cancer. Based on this observation, Heidelberger вЂњtargetedвЂќ this biochemical pathway by attaching a fluorine atom to the 5-position of the uracil pyrimidine base, which resulted in the synthesis of the fluoropyrimidine 5-fluorouracil (5-FU). They identified a unique biochemical feature of rat hepatoma metabolism in that there was greater uptake and use of uracil relative to normal tissue. It was not until the middle 1950s that Charles Heidelberger and colleagues at the University of Wisconsin developed a drug that was aimed at nonhematologic cancers ( 26). The 1943 results set off a burst of support for the synthesis and testing of several related alkylating compounds, including oral derivatives such as chlorambucil and ultimately cyclophosphamide. The initial study was done in 1943 but because of the secrecy associated with the war gas program, the results were not published until 1946 ( 16вЂ“ 18). Marked regression was observed in this and other lymphoma patients. When they observed marked regressions, they convinced their colleague Gustaf Lindskog, a thoracic surgeon, to administer nitrogen mustard to a patient with nonвЂ“Hodgkin's lymphoma and severe airway obstruction. Goodman and Gilman carried out experiments in mice bearing a transplanted lymphoid tumor with one compound, nitrogen mustard. Office of Scientific Research and Development and asked two prominent Yale pharmacologists, Alfred Gilman and Louis Goodman, to examine the potential therapeutic effects of these chemicals. Consequently, Milton Winternitz at Yale, who had worked on sulfur mustards in WWI, obtained a contract to study the chemistry of the mustard compounds from the U.S. The experience in WWI and the effects of an accidental spill of sulfur mustards on troops from a bombed ship in Bari Harbor, Italy, in WWII ( 14, 15) led to the observation that both bone marrow and lymph nodes were markedly depleted in those men exposed to the mustard gas. Although gases were not used on the battlefield in World War II (WWII), a great deal of research was done on vesicant war gases ( 5, 8).

Keymo therapy