**5. Drug design for treating cancer**

During 10-year period in the Professor Ross' Lab, I made over 120 such drugs to attack a solid tumor called the Walker carcinoma 256 in rats. The most effective drug was called CB 1954 (2-4, dinitrophenyl aziridinyl benzamide) (see structure in **Figure 1**). It was 70 times more toxic to the tumor cell [14]. It is the most effective drug ever made against the solid experimental tumor for which I was honored with the Royal Cancer Hospital's Institute Cancer Research postdoctoral award. Why mutated DNA must be attacked is because mutated DNAs code for wrong amino acids which produce wrong protein and cause abnormal growth leading to cancers. The reason why we work on mouse model is that if you would compare the genome of man, mouse, and monkey, they are all mammalians and their genomes are very similar. Once you succeed in attacking mouse tumor, it opens gate to attack human tumors. Now, you know how challenging it is to shutting off a mutated gene and how easy it is to introduce mutations in the same gene by smoking.

44 Prevention, Detection and Management of Oral Cancer

The good news about smokers is that they could see their own genome on their computers and could also see the progress of mutations of their own genomes before and after smoking. Now, I do not have to tell my best friends not to smoke. All I have to do is to give the two CDs of their genomes and let them see for themselves. Let them see on their own computers and compare the two genomes. First, CD taken soon after their birth and second taken after they become smokers. Before I talk about the sequence-specific tumors of oral and lung cancers, let me share with you how our genome, the book of our life, looks like before you smoke.

The basis of OC is that people who are chewing tobacco or inhaling burning tobacco by smoking (as in India) or chewing betel quid, betel nut, etc. (as in Taiwan) causing major mutations in their genomes producing a host of chemicals which damage the normal function of the cell causing them to become abnormal or cancerous. To understand the molecular basis of cancers, we have to sequence the normal as well as cancer cell genomes for comparison.

To refresh your memory, I repeat. Carcinoma is the most common type of cancer. It begins in the epithelial tissue of the skin, or in the tissue that lines the internal organs, such as mouth, oral cavity, reparatory tract, and lungs. There are 220 different types of tissues in the normal human being. We have sequenced (read letter by letter the entire script of nucleotides, their numbers, and their orders in which they are arranged). After genome sequencing, we can compare with the sequence of oropharynx carcinoma with normal cell from nonsmokers. I am happy to inform you that we just completed the Thousand Genome Project. Now, we can compare thousands of the same mutated sequence a time. We can locate the specific mutations with precision and accuracy. To locate specific mutations, in all oral cavity cancers, similar comparison can be studied in several types of salivary gland cancers including adenoid cystic carcinoma, mucoepidermoid carcinoma, and polymorphous low-grade adenocarcinoma.

Once a mutation is identified in a specific oral cancer, my job begins trying to find a dye which colors these tumors. Once a dye is found, I could attach the toxic groups to shut off their genes. There are hundreds of dyes and there are hundreds of their combinations. With AT and GC, four nucleotides of DNA, I get 64 combinations; imagine how many combinations I get from hundreds of dyes. Fortunately, there are finite combinations. I could find it. Suppose I want to design drugs to treat cancers of the oral cavity. The cancer begins in the epithelial tissue of the skin, or in the tissue that lines the internal organs, such as mouth, oral cavity, reparatory tract, and finally reaching lungs. We have been designing drugs to attack toughest solid tumor like

Tonsils and base of the tongue tissues also develop lymphomas.

Firtz Heber, a German Army officer, worked on the development of chemicals as a weapon of war. He was responsible for making deadly nerve gases and nitrogen mustards. Before the WWI, he was honored with a Nobel Prize for capturing nitrogen directly from the atmosphere by burning the element magnesium in the air forming its nitride. Upon hydrolysis, nitride is converted to its nitrate which is used as a fertilizer. Using this method, we could make unlimited amount fertilizer. Nitrate is also used for making explosive. Soon after the WWI, Heber was charged with a crime against humanity for releasing hundreds of cylinders of chlorine gas on the Western front killing thousands of soldiers in the trenches. When allied forces reached his residence, his son shot himself and his wife committed suicide. Heber went in hiding in Switzerland. After the war, German government got his release as a part of the peace negotiations. Heber returned home to hero's welcome. Although he promised never to work on the nerve gases again, secretly he continued to develop more lethal analogs of highly toxic nitrogen mustards. It was Heber who first made the notorious bis-dichloroethyl methyl amine. Because it smells like mustard seeds, it is called as nitrogen mustard. During the next 20 years, before the beginning of the WWII, hundreds of more toxic analogs of nitrogen mustard were developed. The bad news is that they are highly toxic and the good news is that they shut off genes.
