Chemotherapy el pt

Multi Drug Resistance to Chemotherapy

Date: July 25, 2024

by Chaya Venkat

A Significant – and Inevitable – Obstacle

Related Articles:

Clonal Evolution;
Fludarabine.

Some of us swear we will never accept chemotherapy, never put our bodies through all that toxicity. Guess what, I would like to take a bet with each and every CLL patient: when push comes to shove and he or she is faced with the alternative of sleeping six feet under, every one of us will decide to accept chemotherapy. And as far as CLL is concerned, no other drug is as important as fludarabine, either by itself or in combinations such as RF and RFC. Hopefully that will change down the road, and we will have totally "non-chemo" choices that give fantastic response rates. That day is not here, not yet. 

When oncologists discuss prognosis, the term "fludarabine refractory" has an ominous ring to it. Correctly so, people who do not respond to fludarabine therapy have far fewer options down the road. As we have been discussion in the past few days, Rituxan is not a good option for some patients, especially if they are no longer naive. The monoclonal tags the CD20 positive cells alright, but without an effective cell kill mechanism of its own, and a weakened immune system unable to provide the necessary fire-power, the resulting cell kill is less than impressive. It is as if the undercover snitch tagged the criminal OK, but there is no police force around capable of taking him down. This is why fludarabine is so important, it is one of the best cell kill agents out there. It is not exactly a kind and gentle chemo drug, a lot of innocent bystanders get killed too as it takes down the hunted cancer cell. As a tag team, Rituxan the snitch and fludarabine providing the  fire-power, the combination is hard to beat. 

Which is why it is no joke when patients become refractory to this all important drug fludarabine. Unfortunately, patients who develop resistance to one drug often develop resistance to several other related drugs as well, in what is called "Multi-Drug Resistance syndrome" , affectionately called MDR. (I think doctors and scientists are born with a genetic defect that makes acronyms and jargon irresistible to them). The good news with MDR is that therapy choices become a lot less complex; the bad news is that there are not too many effective therapy choices left to dither about.

Article:

This paper (URL below) is one of the most interesting I have read in a while, laying out the whole complex weave of MDR. It is well worth the effort to slog through, if you have a couple of hours and the old grey cells are feeling up to it. The full paper can be accessed through the link below, free of charge.  

Blood Journal Article (Free Full-text)

In spite of their seemingly fiendish cunning, cancer cells do not actually 'invent' any of their escape mechanisms, they just steal and subvert existing systems of the body. When used in the correct context, MDR is a very necessary and important function of the body: cancer cells just make a travesty of it for their own ends. That raises the question, why does the body need MDR for proper function? Here is one more of my hokey analogies, I know they send some readers up the tree, so surf to something else NOW if you are one of them. 

Society needs to protect its policeman (T-cells and NK-cells). These guys and gals are in harm's way by the very nature of their jobs (immune surveillance). Our police need to wear bullet-proof vests to protect them from the fire-power of criminals (MDR protection against toxins generated by pathogens). Sometimes, the vests come in handy to protect the cops against "friendly fire" of other cops, or accidentally shooting themselves in the foot (MDR against toxins generated by the T-cells themselves, in trying to kill the pathogens). 

There are also special places like the courthouse (liver, colon, kidney, etc.) where by the very nature of the criminals streaming in all day long for processing (all three organs serve a critical function of getting rid of the accumulated toxic wastes from the body), we need guards stationed around the building who also have bullet-proof vests to protect them from the riff-raff (epithelial cells lining these organs also have MDR protection, so that they can survive the toxins they handle routinely). These buildings of civic pride have to be protected at any price (MDR protection for immunologically privileged sites like the liver and kidneys is a must). 

There are other buildings like the White House and Senate (brain) that need to be protected, not because there are a lot of criminals milling around (!) but because the site is so darn important to proper functioning of society. Hence the need for secret service agents with bullet proof vests and the license to kill (cells that form the blood-brain barrier are MDR protected, so that few toxins can break through this line of defense). 

OK, you get the picture. MDR is a necessary system to protect the specific cell lines of the immune system that have to do the hard work of killing pathogens, and privileged sites like the brain and liver from exposure to toxins. Incidentally, this is what makes brain cancer so hard to treat with chemotherapy, the MDR protection does not let too many drugs cross the blood-brain barrier and get to the tumor site where it may do some good. Radiation and surgery are more the norm for brain tumors. 

So, how does this MDR work? Here is another mental picture. When we lived on the East Coast, sometimes during the rainy season it would rain non-stop for several days. The ground outside our house would get soggy and saturated with water, puddles everywhere. The first year, our below-grade basement got flooded, it was a huge mess to clean up. The excess water outside seeped  through the walls of the basement; the more the water saturation outside, the greater the seepage into the basement. 

The next year, we installed a sump pump. It rained cats and dogs that year too, but no problems with flooded basement! Soon as some of the water came in and collected in the sump, the pump switched on and pumped it right back. 

That is pretty much how MDR works. Cells that have MDR protection, whether they be legitimate users of the technology like T-cells or thieves who stole the bullet proof vests like cancer cells, all of them express a protein called P-glycoprotein, also called P-gp. This acts just like a sump pump. Even at high concentrations of the chemotherapy drug on the outside of the cell wall, the P-gp can pump it out as quickly as it gets into the cell. Net result, other innocent cells in the neighborhood are dying in droves because of the toxicity of the high dose chemotherapy drug sloshing around in the blood and tissue, but the cancer cells with MDR protection keep chugging away their little P-gp pumps, keeping the concentration of chemo drugs nice and low within their cell walls, and living through the experience just fine. This drug resistance at its worst, when the toxic side effects are still there in full force, killing good cells in your body but not doing much of anything to the cancer cells. 

So how do the cancer cells get hold of the MDR technology? Continuing with our analogy, initially the criminals (cancer cells) are ignorant (chemo 'naive'), and they get killed in vast numbers (good response to therapy) either by the police bullets (T-cell cytotoxicity) or poison gas (chemotherapy). But with each generation of crooks, the dumb ones are killed most easily, and the smart ones tend to escape. Pretty soon, just the process of weeding out the dummies means we have now a criminal class that can figure out how to escape the just wrath of society (there is a selection of more drug-resistant cancer cells with each round of chemo). Pretty soon they figure out how to steal the bullet proof vest technology (MDR protection), it helps them that they did not have to invent bullet proof vest technology, just steal it for their own purposes. (MDR is a well established and necessary invention of the body, inappropriately used in cancer drug resistance). In some cases, if the criminals are part of the police force, good cops gone bad, (the cancer cells are themselves a part of the immune system, as in CLL), they don't even have to try hard to steal the bullet proof vests, some of them may own the vests already (some cancer cells are drug resistant from the get go). 

Multi-drug resistance (MDR) is a significant obstacle to the success of chemotherapy in many cancers. In addition, MDR can occur in some cancers without previous exposure to chemotherapy agents. The chemo drugs that are most frequently associated with MDR are paclitaxel, docetaxel, vinca alkaloids like vinorelbine, vincristine, and vinblastine, anthracyclines like doxorubicin, daunorubicin, epirubicin, epipodophyllotoxins like etoposide, teniposide, topotecan, dactinomycin, and mitomycin C. Some of these are relevant to us as CLL patients, others are used more commonly for solid tumors. 

The expression of P-gp is usually highest in tumors that are derived from cells that normally express P-gp, such as epithelial cells of the colon, kidney, adrenal, pancreas, and liver (think of our example of bad cops with ready access to bullet proof vests), and here drug resistance may happen even before chemotherapy is started. In other cancers, the expression of P-gp may be low at  the time of the start of the cancer, but increases after each bout of exposure to chemotherapy agents, until full blown MDR is established. 

Many of the early agents that reversed the effects of the P-gp pump, such as verapamil, and cyclosporin A, tamoxifen etc., had one little problem: these agents had to be used in high dosage to be effective, and they were toxic as all heck at these dosage level. You see, the way these agents worked was by literally overwhelming the capacity of the P-gp pump. If so much of this agent is flooding into the cell, the P-gp pump cannot get rid of the agent, as well as get rid of the chemotherapy drug it was trying to pump out in the first place. You can see how this strategy will need lots  and lots of the MDR reversing agent, and this may not be so good by way of toxicity.  

Some of the newer agents in clinical trials to try and control MDR seem a lot smarter. One of them is tariquidar, which binds with high affinity to P-gp pump, literally gumming up the works so that  the pump can't pump anything any more. There are even some monoclonal antibodies being developed that target the marker associated with the P-gp pump protein, and deactivate the pumping action by virtue of tagging the protein. 

As always, this has been an overly simplified picture of a very complex subject. But it is close enough to reality that you get a good feel for how cancer cells develop resistance to many of the chemotherapy drugs we need to use to control them. Using the simple and elegant process of pumping out the chemo drug as fast we try to pump it in, the cancer cells neatly turn the tables on us, using the very mechanism our bodies have developed to protect its immune defenses. The more I learn, the more fascinating is the endless detail in this death struggle between cancer and the health and survival of our bodies.