books book reviews

cancer biochemistry and drug development

reviewed by T. Nelson

Score+5

Targeting the DNA Damage Response for Anti-Cancer Therapy. (Cancer Drug Discovery and Development series)

by J Pollard and N Curtin, eds.
Springer Nature, 2018, 400 pages

reviewed by T. Nelson

“Americans crave tales of adventure, mystery, love and tragedy as a summer rite of passage,” writes one commentator before giving us a list of sappy novels for the Fourth of July. Screw that. Here's a great book on cancer.

Chemotherapy started during WWII, when the Germans bombed the Allied fleet in Bari, Italy during WWII, killing over a thousand Allied troops. Historians call it Little Pearl Harbor. One of the ships, the John Harvey, was carrying a number of 100-pound bombs filled with mustard gas, known as sulfur mustard, because it was feared that the Germans might resort to chemical warfare.

Military doctors examining the 83 who died from mustard gas exposure found that they all showed a loss of white cells, or leukocytes, causing leukopenia. The doctors theorized that nitrogen mustard might protect against leukemia, where there are too many leukocytes. This led to the first chemotherapeutic agent and the founding of the Sloan-Kettering Institute for Cancer Research. It also marked the beginning of oncology's war on DNA, which is the subject of this highly technical but fascinating book.

Chemotherapeutic agents, based on the original mustard gas finding, are designed to cause DNA damage. Cells respond to DNA damage by trying to repair it. There are two pathways, depending on whether one or both strands of DNA are broken.

If a single strand is broken, the ATR signaling pathway activates a complicated series of molecular events to repair the DNA. Usually the cell is successful. If something goes wrong, or if the DNA damage is too severe, the second strand may also break. In this case, the cell activates other processes such as homologous recombination or non-homologous end-joining, which is an error-prone repair. Should this also fail, the ATM signaling pathway activates tumor suppressor protein p53, which decides whether to halt mitosis by blocking the cell cycle or trigger apoptosis, which is programmed cell death.

Chemotherapeutic agents and radiation are indiscriminate: they poison any cell that tries to divide. Cells in the hair follicles and small intestine, which divide rapidly, are also affected, so the treatments cause hair loss, nausea, and vomiting, and sometimes produce new cancers. The new drugs block ATR (or sometimes ATM) to increase the efficacy of radiation so less of it is needed. Thus, the new strategy is to block ATR, preventing the cell from repairing single-stranded breaks. Doctors then blast the patient with ionizing radiation to create breaks in the DNA. Since the breaks cannot be repaired, p53 is activated, and the cells that grow the fastest undergo apoptosis.

One challenge is that p53 is the most commonly mutated protein in cancer: when a mutation prevents p53 from functioning, it can't trigger apoptosis, and the cell continues to divide until its chromosomes become hopelessly mangled, at which point the cell dies in an uncontrolled and very messy fashion.

Another challenge is that, because cancer cells mutate, they rapidly evolve. Those that happen to have a mutation that protects them from the treatment continue to grow, and the disease becomes “resistant.” Damaging their DNA accelerates this process, so chemotherapy typically works only once in a given patient.

Caffeine weakly inhibits some of these DNA repair enzymes. This was one reason some early investigators claimed that coffee caused cancer. However, it was soon discovered that the dosage of caffeine needed to increase your risk was so high that you'd die of a heart attack many times over before you damaged any of your DNA.

To those of us whose job is to search for ways to prevent cells from dying, the whole idea of finding ways to kill cells seems bizarre. Oncologists have a tendency to label any protein that promotes cell growth as an oncogene. To them it's just a shorthand. For everyone else, it's a kiss of death: it is nearly impossible to get a drug approved if it is thought, fairly or unfairly, to cause cancer. That means that drug companies don't bother, and many promising drugs designed to promote cell growth have been abandoned because of this.

I know this from experience: I was forced to drop a promising Alzheimer drug because oncologists suddenly started erroneously calling our target enzyme an oncogene.

The first few chapters discuss the molecular biology of DNA repair. Later chapters discuss the medicinal chemistry. It's fascinating stuff and the book is highly recommended, but there's no hand-holding in this book. A background in biochemistry or drug discovery is recommended. Minor points are that many of the drug names and clinical trial names are wrong. For example, Chk1 inhibitor MK8776 is incorrectly written as MK8876 (which is a hepatitis drug), PF00477736 is incorrectly written as PF004777, and MK8776 is incorrectly shown as a WEE1 inhibitor where the authors actually mean MK1775. No doubt this is why drug companies give their products easy-to-remember names. There is no index, so the reader must take copious notes.

july 05 2021

Score+4

The Biology of Cancer 2e

by RA Weinberg
Garland Science, 2014, 876 pages + 64 pages of glossary, abbreviations, and index

reviewed by T. Nelson

What a great way to spend a summer weekend: sitting out in the shade, covered head to toe with sunblock, bottles of vitamin E, quercetin and vitamin C at your side, reading a book about the molecular biology of cancer! What more fun is there than this, I ask you?

Be warned: you won't get this big paperback book for less than $150–$200. Some dishonest online book dealers are selling the DVD by itself, falsely listing it as the “paperback” version. As soon as you click the Order button, the display magically changes from “paperback” to “CD” and you're out 25 bucks.

The DVD (which is included in the book along with a handy wall poster) contains a few video lectures by the author and some powerpoints, but doesn't include the text of the book. Undergraduates, who, I'm told, actually watch TV on their cell phones, will enjoy it.

Well, maybe that's why God created the cell phone, but tremendous progress has been made in cancer research. Even as recently as the 1990s, people were still using the Ames test to test if something caused cancer. Weinberg discusses it somewhat nostal­gically, but it was a colossal failure. The test used special bacteria to test for mutagenicity. We were required to put enormous doses--often approaching the limits of solubility--on the cells, and our Regulatory guy would go into a state of panic if we got a response. The Ames test was a major reason why we have those amusing warnings on everything saying it's “known to the state of California” to cause cancer. Eventually Bruce Ames himself spoke out and denounced his own test, and the test has been mostly abandoned.

This book describes the biology reasonably well. The discovery of oncogenes, receptors, and checkpoint inhibitors in the search for the causes of cancer revolutionized molecular biology, and now we're starting to get clues as to what extra pieces might be needed as oncology starts to recognize the central importance of the immune response and comes to see cancer in the wider biological context of DNA damage. Cancer seems to be poised for a conceptual breakthrough.

This is a history-oriented depiction of cancer biology suitable for an under­grad­uate or layman. It's a bit light for a graduate-level course, and since it was published in 2014 much of the material has started to become obsolete. But it will give you a clear view of the current dogma and how we got there. That's something you have to know.

july 18 2021