Chemotherapy is a very common way to treat many types of tumors, but chemical treatment of brain tumors is made difficult by the blood-brain-barrier which protects the brain from pathogens, but usually also hinders treatment, requiring novel delivery methods.

• Bibliography

Types of action

As cancer cells are different from regular cells by not respecting the regular cell-death mechanisms and constantly dividing, chemotherapy aims to remedy this by either preventing further division of cancerous cells or activating the broken cell-death mechanisms.[1][2]

Cytostatic chemotherapy

This kind of therapy concentrates on changing the chemical balance in the tumor site in a way that doesn't allow further cellular division of cells and so stopping the growth of the tumor. Another possible course of action is stopping the angiogenesis (creation of new blood vessels) in the tumor so that more blood and nutrients cannot flow to the tumor. [3]

These medications are usually used as an addition to cytotoxic drugs, as they help prolong the time before a tumor can relapse after being targeted by cytotoxic medications.

• Growth-factor receptor inhibitors - this kind of chemical treatment binds to the cell's growth hormone receptors, inhibiting them and so slowing or stopping the growth of cancer cells
• Anti-angiogenesis agents - these chemicals negate the effects of angiogenesis hormones, not allowing the tumor to signal the need for vascular system growth and thus limiting the supply of oxygen and nutrients from the blood and so stopping the growing potential

Cytotoxic chemotherapy

This type of therapy concentrates on actively killing the tumor cells by activating their cell-death mechanism or changing the chemical environment in the tumor area in a way that doesn't allow cells to survive. Most of these drugs are cycle-specific, meaning they are most effective when the cell in question is in a certain life-phase.

General cell life-cycle

[4]

All cells in our body go through these phases until they are finally too damaged to continue division. When that happens, cell-death mechanisms are applied and the cell dies.

In regular cells, a lot of the time is spent in the G0 resting phase. Cancer cells instead cycle through the phases as rapidly as possible to divide and grow. Cancer cells do not respect the cell-death mechanisms and their life-cycles are typically very short compared to healthy cells. 

Depending on their dependence on the cell life-cycle, chemotherapeutic drugs are classifies into:

Cell cycle–specific drugs – their efficiency depends heavily on the cell state (resting, growing, dividing), but not on the specific phase of the given state

Cell cycle phase–specific drugs – very effective against cells in a specific phase of the cell life-cycle

Cell cycle–non-specific drugs – efficiency does not depend on the life-cycle stage of the cell

Types of cytotoxic chemotherapeutics

• Alkylating agents – irreversibly damage the DNA in tumor cells, rendering them unable to divide – most of these are cycle-specific

• Antimetabolites – stop tumor cells from making enzymes needed for new cell growth – most are cycle-specific, some even phase-specific
• Anti-tumor antibiotics – These drugs inhibit enzymes needed for cell growth, toxify the environment around the cell – usually cycle-non-specific
• Hormones – Block production of crucial enzymes inside the tumor cell
• Mitotic inhibitors – block the production of proteins required for Mitosis (cell division) – cycle-specific to Mitosis state

Delivery systems

There are several dominant approaches being used for chemotherapeutic agent delivery to the brain. [1]

• Systemic Intravenous Delivery – drugs are inserted into the bloodstream, they penetrate the blood-brain barrier and enter the tumor cells. The fact that BBB has to be crossed severely limits the applicability for tumors of the brain

• Systemic Oral Delivery – drugs consumed orally, rarely used in brain chemotherapy due to low bioavailability through this channel and BBB.

• Local delivery – drugs are inserted closer to the tumor, resulting in increased concentration in the area of interest, reduced concentration in the rest of the body and bypassing the blood-brain barrier

  • Implantable treatment - a dose of decomposable drugs is placed in the cavity left after surgical tumor resection. These dissolve within several weeks, killing off cancer cells left after surgery. [5]

• Intracerebroventricular delivery – delivers agents into the brain via CSF and through the brain-CSF barrier

  • Intrathecal delivery (Lumbar puncture) - a spinal tap is performed, a small amount of chemotherapy is injected during the lumbar puncture

  • Intraventricular delivery (Ommaya reservoir) - Works by delivering the drug directly into the lateral ventricle of the brain, through the skull [6}

We discuss several novel approaches for chemotherapy delivery in a separate article.

Side effects

Hair loss, nausea and fatigue are the most common side effects of chemotherapy. [2][7]

Nausea and fatigue are associated with cytotoxic drugs and are caused by the fact that these medicaments damage cancerous cells a lot more than healthy ones, but healthy cells are still being damaged and destroyed. The side effects and their durations vary, but usually persist for several months after the treatment.

Cytostatic substances on the other hand impede the division of cells, so many quick-dividing, renewable structures of the body stop functioning properly. This is most obvious in hair-loss and damage to mucous membranes in the body.

Chemotherapy also damages the bone-marrow, causing decreased production of white blood cells, thus lowering the patient‘s overall immunity.

Other symptoms are common, such as headaches, nausea and pain caused by peripheral nerve damage.

Bibliography

1) How Is Chemotherapy Given?, http://chemocare.com/chemotherapy/what-is-chemotherapy/how-chemotherapy-is-given.aspx (access 29/05/17)

2) Chemotherapy, http://www.abta.org/brain-tumor-treatment/treatments/chemotherapy.html (access 29/05/17)

3) Types of Chemotherapy, http://chemocare.com/chemotherapy/what-is-chemotherapy/types-of-chemotherapy.aspx (access 29/05/17)

4) The cell cycle, http://www.cancer.ca/en/cancer-information/cancer-101/what-is-cancer/the-cell-cycle/ (access 29/05/17)  

5) Perry J. et al. (2007) Gliadel wafers in the treatment of malignant glioma: a systematic review, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2002480/ (access 29/05/17)

6) Ommaya Reservoir Patient Education, http://healthlibrary.stanford.edu/patient/ommaya.pdf (access 29/05/17)

7) Side Effects of Chemotherapy, http://www.cancer.net/navigating-cancer-care/how-cancer-treated/chemotherapy/side-effects-chemotherapy (access 29/05/17)