Saturday, May 14, 2016

Everybody loves an anti-cancer drug

There are over 19000 papers, published till date, with the word anti-cancer in title or abstract. Over the years, funding for research on newer anti-cancer drugs has increased. So is the publications with this phrase (See the figure below). This phrase also have some magical power. It helps me to easily justify my research and grab a slice of funding pie. Unfortunately, the pie is never enough for all. 

Unfortunately, we are still far from wining the disease. 

Plot showing trend in publication of papers on "anti-cancer". Pubmed was searched for all the papers having the phrase "anti-cancer" either in abstract or in title. The numbers in parenthesis show the year of first report.

Working for drugs against cancer has some technical advantages over other diseases. Think about developing a new drug for an infectious disease, like Dengue or Malaria. It’s difficult to have a good in vitro model for many infectious diseases. When you have one, you need special laboratory facility and legal clearances to work on those. 

Cancer research has no such troubles; at least at the early stages of the project. Most of the in vitro assays are performed on cell lines. HeLa was the first human cell line, reported in 1952. Since then cell lines are the workhorse of anti-cancer drug development. These cells are treated with a drug and its ability to kill these cells is measured. Some time the drug does not kill the cell but just stops the cell division. That’s good enough for us. Measuring such cytotoxic or cytostatic effect of a drug is not so difficult. We have many cheap and reliable assays for this. One such is the famous MTT assay.

These experiments are simple, cheaper and you don’t have much legal and ethical issues. For a scientist, these are critical determinants. Social priority, science policy, academic fashion and ease of preliminary experiments, all these are behind the exponential growth in publications on anti-cancer agents.

But what is an anti-cancer agents? A search through the Pubmed throws up curious mix of items: plant extracts, nanomaterials to  atmospheric gas plasma. Most of these studies involve some form of in vitro cell culture-based experiment to show that these materials kill the cells, preferably through apoptosis. Essentially, the authors are checking cytotoxicity of these agents. Interestingly, some of these materials are also toxic to bacteria and often promoted as bactericidal agents, albeit in separate papers.

Most of these anticancer agents never makes to next step of evaluation. No body chase them further, not even the inventors. Authors move to another project, on another anti-cancer drug. Another paper is minted with the same key word. 

Cancer is a cellular disease. It is a disease with cells having genetic, epigenetic and phenotypic changes. To treat, either we have to convert these cells back to normal  or we have to get rid of them. For the time being, the first one seems improbable and our focus is on the other option.

In 1947, Sydney Farber used the same principle, when he used  aminopterin to treat children with leukemia. Aminopterin stops cancer by blocking cell division. Chemotherapeutic agents, developed subsequently, have the same property. They block proliferation of human cells through diverse mechanisms. Blockage of proliferation hits cancer cells and any other rapidly dividing normal cells. So, these drugs have some sort of inbuilt specificity: they block cell division and affect dividing cells more than those seating idle. 

However, many anti-cancer agents reported in academic literature do not follow the same logic. Something can be cytotoxic for different reasons. It may kill cells by blocking essential  processes like protein production. Cells can be killed by forming pores on the membrane or by oxidative damage. Many so called anti-cancer agents kill cells by these mechanisms. These methods have no specificity towards cancer cells and would affect every other cells in body. Even then, authors call those as anti-cancer agents. 

In fact. we really don’t have shortage of such non-specific cytotoxic or cytostatic agents. I will say, we have enough of such arsenals; enough to stop further search for new one. The focus should be more on developing strategies to deliver those specifically to cancer cells, sparing the normal one.

Academic research has its own dynamics. Some works on basic “blue sky” questions on how nature works. Others prefer to work on issues that has immediate social relevance. Discovery of a new cancer drug would have immediate social impact. Many of us may have such high goal, but we are mostly lost in closed alleys. 

Drug development is always an uncertain endeavor. Something that worked well in vitro may fail miserably in animal experiments or in clinical trials. Even then, our efforts should start with clear logic. Our strategy should have clear rationality based on our existing knowledge of other ant-cancer drugs. Unfortunately "logic" is loosing to the rush to get published. It is loosing to the fashion in academics. 

As the rogue cells keeps dividing within millions of people, we keep trying new methods to checkmate them. We keep trying, often, even without rationality. And the printing press churn out "Anti-cancer" in black and white.