Cancer Chemotherapy

chemo

Of the many diseases in existence, cancer is one of the most interesting and most chose by students for research. Though some may consider it to be overrated I still think it is an interesting condition. Despite this, if one looks at the disease superficially there is nothing truely that over the top about the illness. I often image cancer to be like a computer program. In a computer program if you enter a specific command you know what the obvious output will be. The same is the case with cancer. The “awesomeness” of cancer lies in its molecular biology, not in its genetics or its chemotherapeutic treatment.

What I mean to say is cancer is a genetic illness and the result of a mutated gene is pretty obvious. If a gene that controls the rate of division is affected it is obvious that the cell will divide uncontrollably. An obvious outcome. This is cancer.

By definition, cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells. It is not one single disease as one wrong assumes it to be so.

To understand chemotherapy of cancer one must first master cell cycle and apoptosis (link to understanding apoptosis).

Note that in cancer therapy chemotherapy is just one of the treatments and that there are many others too like radiotherapy and biological which are already in use. And still others like Nanomedicine which are under research.

When we talk about chemotherapy of cancer we talk about cell cycle specific and cell cycle nonspecific drugs. There are numerous other ways to look at the classification that will be talked about later in more advanced lessons/writings.

The two main important points to be noted here are that cell cycle-dependent drugs are schedule dependent and that they target all dividing cells.

anti-cancer-drugs-12-638

Whereas cell cycle independent cells will attack both proliferating as well as non-proliferating cells, also here the treatment is dose-dependent and not schedule dependent.

One must not confuse treatment cycles with schedule dependency.

cell cycle dependant

 

Classification:

 

Alkylating Agents:

These what I to call the original anticancer agents. When people talk about chemo “in the olden days” they are generally referring to these bunch of drugs.

These drugs specially nitrosoureas were used in chemical warfare in WW1. The scientists who worked to research their effects during the war had already discovered their anticancer potential during the war itself but could not disclose it to the scientific community due to contracts with their states. Secrecy was key. Much after the war all was revealed and published and we then got these agents. They are some of the first anticancer agents to be used.

Alkylating agents are subclassified as follows:

Nitrogen mustards: Cyclophosphamide, melphalan, chlorambucil, Ifosfamide

Nitrosoureas: Carmustine, Lomustine

Alkyl sulfonates: Busulfan

Mechanism of Action:

Alkylating agents work by DNA alkylation. That is, they form alky bonds between the nucleotides of the DNA. Since cancer cells divide all the time their DNA succumbs to multiple errors during replication due to the alkylation and thus the cells undergo apoptosis.

Alkylating agents like most regular chemotherapeutic agents do not discriminate between cancer and non-cancer cells and thus have an adverse effect on the patients.

 

Antimetabolites:

Drugs such as methotrexate, Pemetrexed, Floxuridine, Cytarabine, 5-Fluorouracil and 6-Mercaptopurine are examples of these classes.

Mechanism of action:

Agents such as 5-FU and 6-MP work by interfering with DNA replication, they get utilized instead of natural nucleotides and thus cause halting of cell division in S phase of cell cycle. They get used instead of natural nucleotides and halt the process of replication.

Other antimetabolites like methotrexate work to inhibit the dihydrofolate synthesis so as to halt synthesis if purines and pyrimidines.

 

Anticancer antibiotics:

Anthracycline antibiotics: Daunorubicin, Doxorubicin, Epirubicin, Idarubicin

Non- anthracycline antibiotics:  actinomycin-D, Bleomycins, Mitomycin-C

Mechanism of action:

Popularly referred to as stacking or intercalating agents. These drugs work by inserting itself between the DNA bonds they also work by inhibition of the enzyme topoisomerase. This prevents the DNA from closing itself after opening and thus halts replication. Often the intercalation will cause histone eviction of the DNA. This applies mainly to anthracycline antibiotics

Bleomycins work by incorporating a break in the DNA strands in an oxygen-dependent manner. These are a group of compounds, unlike other agents.

 

Microtubule Inhibitors:

Taxane family: Paclitaxel, docetaxel

Vinca alkaloids: Vincristine, vinblastine

Mechanism of action:

Taxanes work by stabilization of cellular microtubules such that its disassembly cannot occur. This inhibits the cell division at M phase directing it to apoptosis.

Vinca alkaloids, unlike the previous class work by inhibition of the formation of microtubule itself.

 

Steroid hormones and antagonist:

These are synthetic hormones or the antagonist of natural ones. Certain cancers posses the receptors for hormones are thus stimulated for growth by the respective ligands of the same.

We can block this action using an antagonist. In other cases, the use of an agonist at the right receptor can cause the stop of tumour growth. It depends on the type of cancer and its receptor expression.

Miscellaneous agents:

Other agents are those such as cisplatin, carboplatin, asparaginase, topotecan cannot be placed in the above classification. From an exam point of view, these are not very important. However, from entrance exams, viva these are often popular choices. Especially platinum-containing agents.

Hydroxyurea also is known as hydroxycarbamide is a unique agent that is used in some cancers. It occurs naturally in low amount in human blood in drug form, of course, it is used in higher doses. It works by inhibition of ribonucleotide reductase.

classification

 

Chemotherapy resistance:

Cancer cells are always multiplying, due to the high rate of multiplication, there is constant mutation of DNA. These mutations are considered to be random. Cancer cannot think, it does not direct the mutation to occur at a certain location to favour its survival. It happens at random.

The mutations occur at such extent that eventually if the DNA analyzed it does not match at all to the that of the patient. Even the chromosome number and structure will not match.

It is these mutations that cause cancer to become resistant to chemotherapeutic drugs.

In some cases, genes may be amplified thus causing amplification of certain enzymes.

In case of certain tyrosine kinase or similar enzymes, the protein structure may be altered such that, the drug will not bind to the protein. There may also be the production of certain proteins that pump out the drug whereas in other cases drug receptors itself won’t be expressed.

Despite having no brain of its own and being based on sheer luck and randomness cancer appears outwardly to be an intelligent disease.

 

 

 

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