Note (9/2003): I began this page to discuss new research in cancer treatment. Later, I realized that it's simply too ambitious a project; however, the topics discussed here might be of interest to someone so I'm keeping the page up. 5/99: all the links here still work, and work is still being done in these research areas.
Mayo Clinic Good News Page (1993) Talks about new advances. General article. (still online in May 1999).
Apoptosis is the process by which cells kill themselves. Usually, cells that have gone wrong, like cancerous cells, will commit suicide. This is a natural protection mechanism for the body.
Researchers have found a cell protein that guards cells against cell death. Called "survivin", this protein is encoded by a human gene which is used primarily during fetal development. This gene is turned off in normal adult cells, so that they do not produce survivin and the cells die if they become cancerous.
The researchers showed that cancer cells grown in the lab always contain survivin, as well as human fetal tissues, such as kidney, lung, and liver. However, adult tissues such as lung, liver, brain, blood, and heart do not contain survivin. The only adult tissues survivin was found in were the thymus and the placenta.
The researchers also studied tissue from lung, colon, pancreas, prostate, and breast cancers. They found survivin in each of these tumor samples. Survivin was rarely present in less aggressive forms of non-Hodkin's lymphoma but was abundant in the most dangerous ones.
The researchers are now examining whether survivin helps cancer cells to resist chemo drugs. Other researchers are studying the mechanism by which survivin halts cell suicide.
What can this mean to leukemia patients? Hopefully they will soon test leukemia cells for survivin. They may find increased levels of survivin in leukemia cells. If so, they can look for a way to inhibit survivin, and therefore the leukemia cells would die. If survivin is turned on during chemo, the potential for inhibiting survivin during chemo exists.
"Science News", 8/9/97, Vol. 152, p. 85. This article refers to an article by Grazia Ambrosini of Yale University School of Medicine in the August "Nature Medicine" and an article by John C. Reed of the Burnham Institute in La Jolla, Calif., in the July 17 "Nature".
Apoptosis is also the object of several other research directions. An article on the Web briefly reviews recent apoptosis reports "Apoptosis Provides New Targets for Chemotherapy". The following paragraphs are my interpretation of the Web article.
Klaus-Michael Debatin in the Department of Hematology/Oncology at the University Children's Hospital in Heidelberg, Germany, states that they used to ask why tumors resist chemotherapy, but now they are asking why they are sensitive in the first place. Chemotherapy damages all cells that are dividing when the treatment is given; all of these damaged cells should then commit suicide. As described above, this is apoptosis, the cascade of molecular events that ends in shredding repair proteins, structural proteins, and the genetic material. Chemotherapy should kill all the affected cells, but it does not, some or all may resist cell death. This may be because apoptosis is not turned on in a sub-population (or all) of the cancer cells.
They know that the chemotherapy drugs damage the cell; this damage should be irreversible: why isn't it? Because apoptosis fails.
Although the field of apoptosis study is quite new, it has exploded in the last 2-3 years. Debatin published an article in the May 1997 Nature Medicine delineating the role of a receptor called "CD95" (also known as "Fas"). CD95 and its ligand cause apoptosis - they are the good guys. They know that CD95 is involved in the pathway to apoptosis in cells exposed to doxorubicin because they prevented the expression of this gene and then doxorubicin did not cause cell death. They have found the CD95 system of apoptosis in human leukemia T-cells and also neuroblastomas.
In 20-30% of patients who relapse, they find the relapse especially hard to treat. Debatin believes that the resistance is because these cancer cells have mutations in the CD95 receptor.
Researchers are looking into means of activating CD95 using a drug much more specific to this receptor than doxorubicin, which can cause mutations itself.
CD95 is not the only place in the apoptosis pathway under study. Another protein being studied is the Bcl-2 protein. Finbarr Cotter at the University of London is conducting a phase I study using an antisense molecule that binds to the mRNA which codes for the Bcl-2 protein. Thus, Bcl-2 is not produced. Although they are not yet up to the therapeutic range, they haven't yet found the new drug toxic to humans.
The tumor suppression gene P53 is also implicated in apoptosis. Tumors with a p53 mutation generally have a poorer chance of being cured than tumors with normal p53. Most chemotherapeutic agents as well as radiation work on cells with intact p53 protein, however, one agent, paclitaxel, works best if p53 is mutant. Combination chemotherapy might successfully kill all the cancer cells.
This article is currently on the Web, although it may not remain there for a long period of time.If you are interested in following this research, search for new articles by the researchers listed above.
Telomerase is an enzyme which keeps chromosomes in "good shape" so that the cells can divide. Most human cells do not contain active telomerase, because our cells do not need to divide indefinitely.
Telomers are short sequence repeats on the ends of chromosomes. As the cell divides successively, the telomers shorten -- they are not replicated properly, but are sort of "chewed up" a little with each successive cell division. If a chromosome does not have telomers of the proper length, the cell will not divide. This is good and proper, because we don't want our cells to continue dividing.
Telomerase is the enzyme responsible for maintaining these telomers. They have found active telomerase in 85% of human tumors. That means, the cancer cells have healthy telomers and divide out of control. A rush is on in the research community to determine the structure of telomerase and the gene which codes for it. But, how could they study something which is not active in most human cells?
Pond scum. Really, they knew that yeast and ciliates contain active telomerase, so Tom Cech's group at the University of Colorado, Boulder, Department of Chemistry and Biochemistry (yes, btw, that's where I work!) grew lots of ciliates, or pond scum. They already knew that telomerase is made up of an RNA subunit and protein subunits. The RNA subunit provides the template for addition of the telomers, but they hadn't been able to find out much about the protein subunit. Now, as the article in the August 15 1997 Science reports, they have isolated the active protein subunit and found the gene which codes for this protein.
Telomerase was purified from the ciliate Euplotes aediculatus and found to contain two proteins, designated p123 and p43. The p123 protein was similar to a telomerase-active protein isolated from yeast, Est2p. Both p123 (ciliate) and Est2p (yeast) have RT motifs, meaning that they are similar in some areas to reverse transcriptase, an enzyme which makes DNA from RNA (the "reverse" of the usual method, which is making DNA from DNA or RNA from DNA). Thus, they suspected that the p123 protein catalyzed the synthesis of DNA using the RNA template to make telomers. In other words, they suspected that p123 was the active protein subunit of telomerase.
They then took p123 RT motifs and used them as primers in polymerase chain reaction amplification of the yeast S. pombe DNA. In other words, they took the total yeast DNA and used the p123 RT motifs to amplify DNA which coded for the p123 protein. They found what they were looking for in a 120 base pair unit. This 120 base pair unit encodes a peptide sequence homologous to both p123 and Est2p. Ta da! Further study using this 120 bp unit a a probe and (a bit more science . . . ), and they have a "putative telomerase reverse transcriptase gene, trt1+". This gene encodes a basic protein with a predicted molecular mass of 116 kD and has a sequence very similar to p123 and to Est2p.
To prove that this gene codes for telomerase catalytic subunit, they deleted the gene from the yeast S. pombe. The cells were not able to maintain their telomers. Again, ta da!
They also searched a human genome database, designated GenBank AA281296, and found a convincing match to the p123/Est2p/trt1P sequence. They have designated this "hTRT" for human telomerase reverse transcriptase. The relative amount of hTRT mRNA correlates well with telomerase activity in in vitro human cell cultures.
The importance of the above described discoveries are several fold. Knowledge about telomerase is likely to lead to methods of inactivating it in cancer cells. Or, they could activate it in mortal human cells and make these cells immortal. Detection of telomerase activity could lead to an assay for early detection of cancer cells. Early detection of cancer nearly always makes a cure more likely.
A group of researchers led by John D. Gearhart of Johns Hopkins Medical Institutions in Baltimore has isolated human embryonic cells. These mother cells, or stem cells, have the potential to develop into any other tissue in the body. They could be used to treat conditions such as spinal cord injuries, diabetes, leukemia, and Parkinson's disease.
Interest in the use of embryonic stem cells from aborted fetuses in the treatment of these diseases has bloomed in recent years. However, the ethical issues involved pretty much rule out the use of cells harvested directly from aborted fetuses. The nice thing about the cells discussed in this article is that they are grown in vitro as cell cultures that have been maintained in the lab for more than 7 months. They would be a renewable source of stem cells.
In a mouse system, blood stem cells are being generated from mouse embryonic stem cells. If the same methods work with human embryonic stem cells, they could eliminate the use of bone marrow tissue or umbilical cord blood to treat blood disorders such as leukemia. Normal bone marrow tissue and umbilical cord blood contain blood stem cells, however, the blood stem cells found in these sources are rare and may not proliferate as well as those derived from the new embryonic cells. Gearhart envisions altering the genes of the embryonic stem cells to make sure that they are not rejected by the recipient, making them the universal donor tissue.
"Science News", 7/19/97, Vol. 152, p. 36. Note: Gearhart has not yet published his work. Thus, it has not yet been subject to peer review.
Update, 5/99: RDF (Radiochemical Development Facility) has a strong research program in and a good web page on alpha emitters. This is an excellent site, with good descriptions and color diagrams of how the process works.
You are most likely familiar with nuclear medicine as "radiation therapy". The body or part of the body of a cancer victim is exposed to a beam of radiation from a radioactive source. All the cells in the path of the radiation are blasted and affected; the cancer cells are affected more than normal cells because they are dividing at the time they are being blasted.
The new nuclear medicine therapies promise to be much more specific to cancer cells, leaving normal cells alone. What they do is attach a radioisotope to an antibody specific to cancer cells. The radioisotope decays, emitting ionizing radiation which blasts the cancer cell.
There are three types of ionizing radiation; alpha, beta, and gamma. Gamma rays are the most powerful; they can pass through the entire body. Alpha and beta particles travel only five micrometers (alphas) to five millimeters (betas) through tissue. All three kinds of radiation have cell-killing abilities, but the alpha and beta particles don't travel as far. So they attach isotopes which emit alpha and beta particles to antibodies which then cozy right up to the cancer cells and attach to them; they aren't interested in normal cells at all. When they attach to the cancer cells, they blast them with their attached radiation.
Since leukemias exist as clumps of no more than a few cells, alpha particles should work quite well to kill them because a large distance does not have to be travelled to reach all the cells in the cancer. Large solid tumore might need betas to penetrate the amss of the tumor.
The problem in the past has been to link the alpha and beta emitting radioisotopes - single atoms - to antibodies - large proteins. To entice these two entities together, they have successfully built a molecular cage compound (cage compounds are the current rage in chemistry, heard of buckyballs?) around the isotope, then use linker molecules to bond the cage to an antibody.
Only a handful of successful marriages of radioisotope to antibody have been made so far. One, however, is iodine-131 (weak gamma and beta radiation emitter) to an antibody which targets the protein on white blood cells and most leukemias. So far, they have used it on teens and adults scheduled to receive bone marrow transplants to arrest advanced leukemias. In addition to the maximum possible whole body gamma ray irradiation, 30 patients were given the new treatment to deliver even more radiation to the cancer cells. They found that it doubled the 5 year survival rate for the 30 patients!
Even though the iodine gamma radiation used in the above procedure is not high, it does mean that the patients remain isolated in lead-insulated rooms for 4-10 days to protect hospital staff and visitors. This is okay for adults and teens, but young children need a parent's touch. The oncodoc developing these procedures, Dana Matthews, is a pediatric oncologist (at Fred Hutchinson Cancer Research Center in Seattle), so she has a special interest in going to the alpha and beta emitters.
David Scheinberg at the Memorial Sloan-Kettering Cancer Center in New York uses bismuth-213, and alpha emmitter, to treat leukemia patients on an outpatient basis. The radiation emitted from this isotope travels only about 3-5 cell diameters. In his Phase I trial (Phase I trials identify maximum tolerable doses), they have already seen significant antileukemic activity.
Most antibody therapies are particularly successful against leukemias as opposed to solid tumors. These cancers are generally smaller and more sensitive to radiation poisoning than solid tumors and they are bathed in the blood that can ferry the injected isotopes. I'd like to quote directly from the last paragraphs of the article:
"Compared to cancers, normal tissues tend to be more sensitive to radiation and chemotherapy. Thus, Vriesendorp notes, oncologists have adopted a 'no pain, no gain' philosophy.
Internally targeted radiation promises a new alternative, he says - 'therapies that don't have to be given at such an industrial strength that they bring the patients to the intensive care unit and close to death.'
Indeed, Spenceley argues, 'if you could learn you had cancer - as horrible as that is - and know that this treatment option was available, then the diagnosis would not be as ugly as it is today.'"
Science News, July 19, 1997, Vol. 152, pp. 40-42. No references to journal articles were given.
First, a little background. Scientists have known since the 1950s and 1960s that tumor cells have unusual chromosomes. The chromosomes are present in greater numbers; they are rearranged by deletion, inversion of segments, or exchange of material between chromosomes. The exchanges are called "translocations" and they became especially important to the researchers when they found that some translocations occurred regularly in certain types of cancers. One of the most famous translocations is the "Philadelphia chromosome", derived from an exchange between chromosomes 9 and 22. The Philadelphia chromosome is found in most tumor cells from patients with CML and some tumor cells of patients with ALL. That is why the research summarized in the following paragraphs is particularly important to leukemia patients.
A research group at Duke University Medical Center led by Ann Marie Pendergast has discovered clues to how the Philadelphia chromosome causes leukemia.
As a cell divides, genetic mixing and matching occurs. Accidents can happen. When bits of chromosomes 9 and 22 are mistakenly snipped off and mistakenly rejoined to one another in a particular order to form the Philadelphia chromosome, the result is that a piece of a gene called BCR is restitched to a large gene called cABL.
Now, this little stitched together gene piece of BCR/ABL contains the blueprints for proteins. It is especially evil because the BCR part contains sequences which permanently activate a part of the ABL component: tyrosine kinase. And, even worse, the ABL segment permanently activates the BCR portion. The proteins get produced and the cell-division machinery is turned on, sending the cell dividing out of control: cancer.
The researchers are studying exactly how the BCR portion takes over the controls of a leukemia cell. Earlier, they found that it triggers oncogenes -- cancer genes -- by affecting a protein called GRB-2. This protein then switches on other enzymes that cause the cell to divide out of control.
But they suspected that the BCR affected other pathways as well. Cells employ multiple pathways to control cell growth, otherwise if something goes wrong, the cell would die. The same is true for an oncogene: it must have many pathways to make cells proliferate.
Now, Pendergast's group has found one more pathway by which BCR works: it interacts with a key cell protein called 14-3-3. Although first isolated decades ago, the role of 14-3-3 in the cell is still uncertain, although biologists now believe that proteins of this type are important links in the process of telling the cell to divide.
The researchers hope that this knowledge will help find ways to stop the leukemia process at the very beginning.