Alimta

[gpawelski]

Alimta (pemetrexed disodium) seems to be a very promising drug. It is sort of like a combination of 5FU plus Methotrexate, only a bit better. This agent disrupts metabolic processes essential for cell production. Toxicity is relatively low. It is not a "me too" drug, but is actually what is called a third generation drugs (of its kind).

It had previously been established that docetaxel improves survival, albeit modestly, compared with supportive care only. A study seemed to show a similar survival with pemetrexed compared with docetaxel, but with lesser toxicity. Expense is horrendous, obviously.

Alimta is a small molecule, folate antagonist (potentiating) drug that can cross the blood-brain barrier. If your cancer cells are "sensitive" (effective) to Alimta, it can work very well at eliminating any brain mets.

Alimta seems to work like Tamoxifen. It may inhibit the P-glycoprotein (gatekeeper in the blood-brain barrier) multidrug resistant membrane pump as well as inhibit protein kinase C (preventing the increase in vascular resistance).

It is not the drugs per se, but rather how they are selected, that change outcomes so dramatically. In this case, it seems like Alimta acts as an agonist (makes the chemotherapy more potent). It can "chemosensitize" tumor cells. It can help chemotherapy be more effective, by being a resistance modifying drug.

Cancer is not a cell, it is a system. Tumor cells are but a small portion of the process of that system. Cancer may represent a response to cellular stress, some of which the oncologist may inflict. The indiscriminate use of cancer drugs may, in some circumstances, be more harmful than helpful to patients.

What is the appropriate dose of Alimta? How should it be given? With what other drugs? Are low doses better than high doses? Personalized therapy is the right treatment, at the right dose for the right patient. Like the weather, however, it seems that oncologists talk about it, but no one is doing anything about it.

In its simplest form, personalized therapy is treatment that is designed to meet an individual's unique biological features. Like a key in a lock, the right drug or combination at the right dosage, opens the door to a good outcome. This is what cell culture assays do, identify sensitivity to the drug or combination, as "unlocking" an individual's response.

As in most things, it comes down to individualization. People will think because they are being completely genotyped, this will give all the answers needed. But it won't. Genotyping will only be of value for drugs for which a gene mutation is informative -- basically KRAS and EGFR mutations -- and we already have tests for those and they are of very limited value. Otherwise, it's a ton of information for which the drug selection value is pretty darn useless.

What's more important than what genes are in the DNA is what genes are actively making RNA, which RNA is actively making protein, which protein is being turned off or turned on, and how all of the proteins in the cell are interacting with each other. The only way to get the latter information, which is ultimately what you want, is to treat the patient with phenotype analysis. In drug selection, phenotype analysis doesn't dismiss DNA testing, it uses all the information, measuring the interaction of the entire genome, to design the best treatment for each individual.

http://www.ncbi.nlm.nih.gov/pubmed/19375814

http://www.ncbi.nlm.nih.gov/pubmed/19632738

http://www.ncbi.nlm.nih.gov/pubmed/22584333

http://www.ncbi.nlm.nih.gov/pubmed/21831719

http://www.ncbi.nlm.nih.gov/pubmed/22887466

[gpawelski]

The blood–brain barrier (BBB), an anatomic structure consisting of endothelial vessel cells, astrocytes and pericytes with tight junctions (TJs) and a number of carrier proteins, controls and limits the passage of molecules to the brain. In the presence of an intact BBB, only small lipophilic molecules (molecular weight [MW] <400 Da) can cross the BBB by diffusion, while the passage of other molecules is regulated by the carrier proteins.

Apart from a few drugs, such as temozolomide, melphalan, carmustine and irinotecan, chemotherapeutic agents, which are large hydrophilic molecules, are unable to cross the BBB, which is furthermore characterized by a high concentration of multidrug resistance efflux pumps, which may be another cause of the low concentration of drugs reaching the site of action.

Recently, Lin et al. underlined the role of astrocytes in preventing chemotherapeutic drugs from reaching metastatic sites in the brain, and observed in murine models that in pathological conditions, astrocytes are activated and come into direct contact with tumor cells, thus confirming the role of the microenvironment in brain metastases (1). This may lead to calcium sequestration, with a *consequent marked reduction in chemotherapy-induced apoptosis.

The role of the BBB in drug resistance has been called into question, since macroscopic intracranial lesions cause BBB disruption due to neoangiogenesis, which produces vessels that lack tight junction molecules and cannot therefore create an effective barrier (2,3).

Nonetheless, BBB disruption may be a characteristic of larger lesions, while the barrier could remain effective in small metastases, as demonstrated by contrast-enhanced images showing enhancement in large intracranial lesions but not in small infiltrative tumors.

Furthermore, the loss of tight junction molecules in the tumor vascular system does not necessarily incur the loss of other biological BBB components, such as detoxification and drug resistance mechanisms, which may remain effective and compromise drug *concentrations in BM (4).

1. Lin Q, Balasubramanian K, Fan D et al. Reactive astrocytes protect melanoma cells from chemotherapy by sequestering intracellular calcium through gap junction communication channels. Neoplasia 12(9), 748–754(2010).

2. Muldoon LL, Soussain C, Jahnke K et al. Chemotherapy delivery issues in central nervous system malignancy: a reality check. J. Clin. Oncol. 25(16), 2295–2305(2007).

3. Papadopoulos MC, Saadoun S, Binder DK, Manley GT, Krishna S, Verkman AS. Molecular mechanisms of brain tumor edema. Neuroscience 129(4), 1011–1020(2004).

4. Lee G, Dallas S, Hong M, Bendayan R. Drug transporters in the central nervous system: brain barriers and brain parenchyma considerations. Pharmacol. Rev. 53(4), 569–596(2001).