Anticancer drugs

Learning objectives: Learn about the drugs that act on central nervous system, their classification and mechanism of action

Anticancer drugs

Cancer:

The term ‘cancer’ refers to a malignant neoplasm meaning new grow.

So, cancer is a disease in which there is uncontrolled multiplication and spread within the body of abnormal forms of the body’s own cells.

It is one of the major causes of death in the developed nations.

The special characteristics of cancer cells:

o        Uncontrolled proliferation

o        Dedifferentiation and loss of function

o        Invasiveness

o        Metastasis

Synonyms:

o        Malignant neoplasm

o        Malignant tumor

o        Carcinoma

Causes of cancer:

1. Chemical agents / Carcinogenic elements:

ü  Aniline causes cancer in bladder.

ü  Arsenic causes cancer in skin, liver and bladder.

ü  CCl4 causes cancer in liver.

2. Radiation:

ü  UV radiation from sunlight and tuning lamp cause skin cancer.

ü  Diagnostic X-ray radiation causes skin, breast, liver, bone cancer.

ü  IR, β, γ, radiation also cause cancer.

3. Heredity:

ü  Breast cancer is seen among female.

ü  Prostate cancer may occur among the male member of a family.

4. Immune system failure:

ü  Carcinoma causes cancer in epithelial tissue.

5. Hormonal deficiency:

ü  Lactrogen deficiency may lead to breast cancer.

ü  Androgen cause liver cancer.

6. Nutritional factor:

ü  Iodine deficiency causes cancer in thyroid gland and breast.

ü  Excessive coffee lead to GIT cancer.

7. Drugs:

ü  Chlorambucil (anticancer drug) cause leukemia.

ü  Chloramphenicol (antibiotic) causes leukemia.

ü  Cyclophosphamide (anticancer drug) causes bladder cancer.

ü  Phenacetin (antipyretic drug) causes cancer in liver.

Treatment of cancer:

There are three main approaches to treating established cancer ...

1.  Surgical excision

2.  Irradiation

3.  Chemotherapy

The ole of each of these depends on the type of tumor and the stage of its development.

Cell cycles:

         An understanding of the cell cycle kinetics is essential for the proper use of anticancer drug/agent.

1. Both normal and tumor cells go through a growth cycle.

2. Normal and neoplastic tissue may differ in the number of cells that are in the various stages of the cycle.

3. Normal tissues are proliferated rapidly (e.g. bone marrow, hair, follicle etc.) are subjected to damage by most antineoplastic drugs.

4. But slow growing tumor with a small growth fraction (carcinomas of the colon) often is unresponsive to cytotoxic drugs. These agents have activity only against cells that are in the process of division.

The cell cycle and relation with anticancer drug action on it is shown below ...

Definition, characteristics of malignant in cancer treatment, cell cycle phase, different types of cancers. Alkylating agents( Meclormethamine, melphalan, Cyclophosphamide, clorambusin, curasin mustard, nitrosourea) read with M/A, toxicity, uses, resistance

Antimetabolites (folic acid analogs, purine and pyridine guelogus)

Antibiotics (actinomycin –D, adriamyacin, daunopubicin, milomycin, bilionycin)

Steroid hormone (Some)

Plant alkaloids (vinca alkaloids, epipodophyllotoxin, cisplatin, taxol – supplied by sir)

Fig: The cell cycle and the relationship of antitumor drug action to the cycle the cell cycle dependent anticancer drugs are listed on the figure at which they act. Drugs that are cytotoxic for cells at any point in the cycle are called cycle phase non-specific drugs.

Cancer Chemotherapy:

When cancer is treated with different types of drugs and chemical agents then process is called cancer chemotherapy.

Drugs used in cancer chemotherapy are as follows.

1. Alkylating agents and related compounds:

ü  Nitrosoureas

ü  Busulfan

2. Antimetabolites:

ü  Methotrexale

ü  Fluorouracil

3. Antibiotics:

ü  Bleomycin

ü  Mithramycin

4. Vinca alkaloids:

ü  Vincristine

ü  Vinblastine

5. Hormones:

ü  Estrogens

ü  Glucocorticoids

ü  Androgens

ü  Progestogens

6.Miscellaneous:

ü  Hydroxyurea

ü  Procarbazine

Common side effects of anticancer drugs:

Tissue or system affected

1. Bone marrow:

a.  ↓ leukocyte production and thus ↓ resistance to infection

b.  Thrombocytopenia

c.   Anemia

2. Digestive tract:

a.  Oral ulceration

b.  Intestinal ulceration

c.   Diarrhea

3. Hair root:

a.  Loss of hair (alopecia)

4. Tissues undergoing repair:

a.  Impaired healing

5. Tumor mass:

a.  Rapid destruction of tumor cell → uric acid ↑→ renal damage

6. Fetus:

                                                                                                                  a.            Depression of growth in children (teratogenesis)

Individual drugs:

1. Nitrogen mustards:

         It is alkalyting agent widely used in cancer chemotherapy.

Name and structure of major nitrogen mustards are given below –

Mechanism of nitrogen mustard:

Nitrogen mustard covalently bonded to the 7-nitrogens of two guanines

The drug forms a reactive cyclic intermediate that reacts with the nitrogen of a guanine residue in DNA to form a covalent linkage

The second arm can then cyclize and react with nucleophilic groups such as a second guanine moiety in an opposite DNA strand or in the same strand → ↓DNA synthesis

Reactions between DNA and RNA and between DNA and protein also occur.

Therapeutic uses of nitrogen mustards (Mechlorethamine):

                                          a.            Extensively used in cancer chemotherapy

                                          b.            In the treatment of Hodgkin’s lymphoma

                                           c.            Carcinoma of the breast, ovary or lung

                                          d.            To treat mycosis fungoides

Side effects:

                                                            a.            Nausea and vomiting

                                                            b.            Local reactions

                                                             c.            Phlebitis

                                                            d.            Bone marrow deplession

                                                            e.            Infection and bleeding

                                                              f.            Alopecia

                                                            g.            Irregular menstruation

2. Nitrosoureas:

         These drugs are both alkylating and carbamoylating agent used in cancer chemotherapy.

Name and structure of major Nitrosoureas are as follows –

Therapeutic use:

1.  To treat tumors in the CNS both primary brain tumor and tumors of metastatic origin

2.  In Hodgkin’s disease

3.  In melanoma

4.  In secondary therapy of non-Hodking’s lymphomas

5.  Effective in lung and colorectal cancers

Side effects:

1.  Nausea and vomiting

2.  Local and phlebitis

3.  Leucopenia and thrombocytopenia

4.  Bone marrow toxicity is delayed dose related, dose limiting and cumulative.

Mechanism of action:

Name and structure of some Alkylating agent:

3. Cyclophosphamide:

Mechanism of action:

Cyclophosphamide itself is not cytotoxic to the cells in culture but can alkylate cellular constituents after metabolized in liver.

Metabolic activation of Cyclophosphamide is as follows –

Resistance to alkylating agents:

         Two general mechanism of Alkylating agent resistance –

o        Decreased drug uptake e.g., methotrexate.

o        Increased repair of the drug defect (DNA repair) e.g., Mechlorethamine.

Resistance to anticancer drug due to –

o        Decreased accumulation of drugs in the cells due to

ü  Cell surface expression

ü  Deficiency of energy dependent drug transport protein

o        Insufficient activation of drug. E.g., mercaptopurine, fluorouracil etc.

o        Increase in inactivation e.g., cytarabine.

o        Increase concentration of largest enzyme. E.g. methotrexate.

o        Decrease requirement for substrate e.g, crisantaspase

o        Increase utilisarion of alternative metabolic pathway e.g., antimetabolite.

o        Altered activity of target, e.g., modified tropoisomerase

o        Mutations in the p53 gene and overexpression of the Bcl-2-gene family e.g., several cytotoxic drugs.

Antimetabolites:

Antimetabolites can be defined as the compounds that prevent the biosynthesis or utilization of normal cellular metabolites. They are structurally related to normal cellular components. They generally interfere with the availability of normal nucleotide precursors (purine, folic acid etc.) by inhibiting their synthesis.

Some of the Antimetabolites are –

o        Folate antagonists e.g., Methotrexate

o        Purine analogus e.g., 6-mercaptopurine, 6-thioguanine etc.

Folic acid analogs:

e.g., Amino protein, Methotrexate

Mechanism of action:

   Folic acid is essential for the synthesis purine nucleotide and thymidylate which in turn essential for DNA synthesis and cell division.

   In order to accept a one-carbon unit and act as a co-enzyme folic acid must be reduced to tetra hydrofolate via reducing dihydrofolate where methotrexate is a potent inhibitor due to its structural similarity with folic acid (structure shown before).

Since T-H4 is converted to a variety of co-enzymes (folinic acd, leucovorin, citrovorum factor) that are necessary for one carbon trnsfer reactions involved in the synthesis of thymidylate, purines, methionine and glycine, inhibition of FH2 reductase can lead to inhibition of DNA, RNA and protein synthesis.

             Fig: Inhibitory action of methotrexate in DNA synthesis.

Therapeutic use:

1.  Treatment of gestational choriocarcinoma

2.  Acute lymphocytic leukemia of childhood

3.  Prophylaxis and treatment of meningeal disease

4.  Osteogenic sarcoma

5.  Epidermal carcinomas of head and neck

6.  Adjuvant therapy of breast cancer

7.  Burkitt’s lymphoma

8.  Mycosis fungoides treatment.

9.  In lung cancer, epidermal carcinoma of the cervix etc.

10.  Non-neoplastic disease

11.  Severe psoriasis and psoriatic arthritis

12.  Polymyositis

Purine analogs:

Mechanism of action:

   For the action against neoplasms, 6-MP must be converted into its corresponding ribonucleotide by the enzyme hypoxanthine-guanine phosphoribosyt transferase. The process is called lethal synthesis.

Thus 6-MP inhibit conversion of 5-phosphoribosyl pyrophosphate to 5-phosphoribosylamine and also inhibit adenylic acid (AMP) conversion from inosinic acid.

↓

Purine base will not synthesized

↓

Ultimately inhibit DNA synthesis and cell division.

The steroid hormones:

Tumors that are steroid hormone-sensitive may be either-

1.  Hormone-responsive, where the hormone regresses following treatment with a specific hormone,

2.  Hormone-dependent, where removal of a hormonal stimulus causes tumor regression, or

3.  Both.

Steroid hormones are not cytotoxic, but modify the growth of hormone dependent tumors. All hormones are only palliative.

Steroid hormones are used in the treatment of –

o        Prostate cancer

o        Breast cancer

Prostate cancer:

         Castration and estrogen administration in the treatment of prostatic carcinoma were preceded by the demonstration of the importance of the androgenic steroids in maintaining normal prostate size and function.

         Castration is followed by marked involution of the normal prostate gland and that this can be reversed by androgen administration.

         The mechanism of the antiandrogenic effect of estrogens is not completely clear. Administration of estrogen to males inhibits the production of interstitial cell stimulating hormone by the adenohypophysis. Since the interstitial cell stimulating hormone promotes testosterone production by the leydig cells of the testis. Estrogens indirectly prevent the synthesis of androgens, thus eliminating androgen stimulation of prostatic growth.

Hormone therapy in patients with cancer of the prostate is never curative.

Breast cancer:

Approximately one-third of patients with breast cancer have tumors that are hormone dependent or responsive. Ablation of the ovaries, adrenal glands or hypophysis or additive hormonal therapy or both constitute effective palliative treatment in these patients.

Small doses of estrogen administration are found to be very effective in reactivating tumor growth, whereas larger, supaphysiological doses are clearly inhibitory.

Thus, ablation of the estrogen-producing glands cuts off the endogenous estrogens. On the other hand, it has been proposed that estrogens at high concentrations act directly on breast tumor cells to inhibit the trophic action of prolactin.

Mechanism of steroid hormone action:

[The steroid hormones are extremely lipophillic and they readily pass across cell membranes to rapidly establish equilibrium between the concentration of free hormone in the cytosol and that in the cell environment (e.g., interstitial fluid, blood, and culture medium).

To have a physiological effect, the hormone must then bind to a receptor protein in the cytoplasm.

After binding, the steroid-receptor complex in the complex in the cytosol is converted to a form that can be bound to acceptor sites in the cell nucleus.

After the steroid-receptor complex is bound in the nucleus, new, specific messenger RNAs accumulation in the cell. This accumulation appears to represt-induced synthesis of mRNA.

It is possible that the hormone affects RNA processing in the nucleus, which could also contribute to the appearance of new mRNA in the cytoplasm. The new mRNA is translated into protein, and in those cases in which a specific protein is produced.

These synthesized protein are not suitable for tumor cells. Thus tumor growing is modified.]

Fig: Mechanism of steroid hormone action.

         After entering the cell (step-1), the steroid binds (step-2) in a stereospecific non-covalent manner to a soluble protein receptor (R) located in the cytoplasm and thus forms a steroid-receptor complex (RS). The complex then undergoes a temperature dependent transformation (step-3) to a form (RSn) capable of binding to acceptor sites in the cell nucleus (step-4). The association of the RSn complex with chromatin in some way causes the synthesis of specific mRNAs (step-5) and consequent new protein synthesis (step-6).

         The newly synthesized proteins produce the cellular alterations that mediate the gross physiological effect.

Drug:

1.  Prednisone

2.  Tamoxifen

3.  Ethinyl estradiol

4.  Diethylstilbestrol

Resistance to steroid hormones:

         About 80% of their resistant lines were marking deficient in binding capacity. The rest were about equally divided between cell lines with normal cytosol binding, which were deficient in their ability to transfer the steroid-receptor complex to the nucleus. Cells with normal cytoplasmic binding and transfer, which were apparently deficient at some step subsequent to the nuclear localization of the steroid receptor complex.

Therapeutic uses of steroid hormones:

1.  Breast cancer

2.  Prostatic cancer

3.  Hodgkin’s disease

4.  Non-Hodgkin’s lymphoma

5.  Multiple myeloma

6.  Lymphoblastic and chronic lymphocytic leukaemia

7.  Mestastic renal cell cancer

8.  Mestatic endometrial cancer

Adverse effects / Toxicity of steroid hormones:

1.  Nausea

2.  Vomiting

3.  Hot flash

4.  Hypercalcemia

5.  High dose causes corneal and retinal opacities

6.  Musculinization (in female0

7.  Fluid retention

8.  Jaundice

9.  Peptic ulcer

10.  Mild fluid retention

11.  Vaginal bleeding

Vinca alkaloid

Vincristine and vinblastine are complex alkaloids derived from the periwinkle plant Catharanthus roeus (also called Vinca rosea).

         They are members of a general class of drugs that act as mitotic inhibitors (“spindle poisons”).

Mechanism of action:

         Vincristine and vinblastine are cycle specific and phaso-specific because they block mitosis in metaphase.

Vinca alkaloids

↓

Bind with the microtubular protein, tubulin is GTP dependent

↓

Blocks the ability of tubulin to polymerize to form microtubules

↓

Paracrystalline aggregates consisting of tubulin dimmers and the alkaloid drug are formed

↓

Resulting dysfunctional spindle apparatus, frozen in metaphase, prevents chromosomal segregation and cell proliferation

↓

Leads to cell death

↓

Inhibits cell division

↓

Cytotoxic effect

a. Normal mitosis:

          Metaphase                                                                            Anaphase

b. Mitosis blocked by vinca alkaloids:

Fig: Mechanism of action of vinca alkaloids.

a. Steady state

b. Polymerization blocked by vinca alkaloids

c. Continued disassembly

Fig Scheme of the vinca alkaloid blockade

a.  “Labile” microtubules, like those of the mitotic spindle apparatus, are in dynamic steady state equilibrium, with assembly occurring predominantly or solely at one end disassembly at the other end.

b.  Vincristine and vinblastine, like colchincine, bind to the soluble 6S tubulin dimmer and the drug dimmer complex ‘caps’ the microtubule, preventing further assembly.

c.   Disassembly continues in the presence of the drug and the microtubule is converted back to soluble tubulin.

Resistance to the vinca alkaloids:

         The resistance may be due to an enhanced active efflux of the drug by a common mechanism.

         Resistant cells have been shown to enhance binding to vinblastine to the P-glycoprotein, which is responsible for the efflux of Vincristine and vinblastine and several other drugs.

         Alterations in tubulin structure may also affect binding of the Vinca alkaloids.

Therapeutic uses of Vinca alkaloids:

1.  Acute lymphoblastic leukaemia

2.  Wilm’s tumor

3.  Ewing;s soft tissue sarcoma

4.  Hodgkin’s disease

5.  Non-Hodgkin’s lymphoma

6.  Neuroblastine

7.  Brain tumors

8.  Rhabdomyosarcoma

9.  Carcinoma of breast

10.  Carcinoma of urinary bladder

11.  Carcinomas of male and female reproductive systems

12.  Solid tumor in children

13.  Carcinoma of lungs and cervix

Adverse effects / Toxicity of vinca alkaloids:

1.  Bone marrow depression

2.  Marrow sparing

3.  Thrombocytopenia and anemia

4.  Thrombocytosis

5.  Neurotoxicity

6.  Arreflexia, foot drop and other signs of motor weakness

7.  Gait disorders

8.  Sensory loss

9.  Deep achinh pain, particularly in the neck and jaw area

10.  Paresthesia

11.  Leucopenia

Cis – Platin

Cis- diamminedichloroplatinum (II):

Cis- diamminedichloroplatinum (II) (DDP) is one of the numbers of platinum coordination complex wit antitumor activity.

Mechanism of action:

         Their mechanism of action is similar to that of Alkylating agents:

Cis – platin

↓

Enters cells by diffusion

↓

The drug loses a chloride ion by –

Hydration

Reaction with nucleophile

↓

Forms reactive intermediate

↓

Alkylating the N7 nitrogen of a guanine residue in one or both strands of a DNA.

↓

Forms inter and intra-strand cross linkages between guanine residues in the DNA chains.

↓

Inhibit DNA replication and transcription and lead to breaks and miscoding

↓

Inhibits both DNA and RNA synthesis

↓

Cytotoxicity

Fig: Two mechanisms by which Cis- diamminedichloroplatinum (II) might react with a nucleophile.

Resistance:(less important):

Sensitivity to these agents is decreased if cells have elevated glutathione levels or increased DNA repair, or if metallothionein (a protein rich in SH group) in induced.

Therapeutic uses of Cis – platin:

a.      Solid tumor

b.      Testicular tumor

c.       Ovarian cancer

d.      Cancers of the bladder, head and neck and endometrium

e.      Some neoplasms of childhood

Therapeutic effect / Toxicity of the cis – platin:

a.  Renal failure

b.  Loss of hearing

c.   Nausea

d.  Vomiting

e.  Anaphylaxis

What is Dactinomycin (Cosmegen)?

Dactinomycin belongs to category of antibiotic  antineoplastic (anti-cancer) drugs. Dactinomycin is a type of cyclic peptides and medication also classified as an “alkylating agent”. Dactinomycin is one of the actinomycins, a group of antibiotics produced by various species of Streptomyces.

Various Types of Anticancer Antibiotic:

Antitumor antibiotics are made from natural products produced by species of the soil fungus Streptomyces.  These drugs act during multiple phases of the cell cycle and are considered cell-cycle specific.  There are several types of antitumor antibiotics:

• Anthracyclines:  Doxorubicin, Daunorubicin, Mitoxantrone, and Idarubicin. 

• Chromomycins:  Dactinomycin and Plicamycin. 

• Miscellaneous:  Mitomycin and Bleomycin.

What this drug is used for:

• Dactinomycin is used to treat Wilms' tumor, rhabdomyosarcoma, germ cell tumors, gestational trophoblastic disease, Ewing's sarcoma, testicular cancer, melanoma, choriocarcinoma, neuroblastoma, retinoblastoma, uterine sarcomas, Kaposi's sarcoma, sarcoma botryoides and soft tissue sarcoma.

Note:  If a drug has been approved for one use, physicians may elect to use this same drug for other problems if they believe it may be helpful. 

Wilms' tumor: dactinomycin in combination with vincristine (Oncovin)and surgery (may include radiotherapy) in treatment of Wilms' tumor

Gestational choriocarcinoma: dactinomycin with methotrexate: maybe curative for localized or disseminated gestational choriocarcinoma.

How this drug is given:

• Dactinomycin is given through a vein (intravenous, IV).   

• Dactinomycin is classified as a vesicant medication, meaning it can cause damage to tissue that comes in direct contact with the drug.  It needs to be given with extreme caution by a qualified medical professional. You should notify medical personnel immediately if you have pain or swelling at the infusion site. 

• The amount of dactinomycin that you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer or condition being treated.  Your doctor will determine your dose and schedule.

Side Effects:

The following side effects are common (occurring in greater than 30%) for patients taking dactinomycin:

• Low blood counts.  Your white and red blood cells and platelets may temporarily decrease.  This can put you at increased risk for infection, anemia and/or bleeding.

• Hair loss (occurs within weeks).  

• Nausea and vomiting (occurs within hours to days). 

• Mouth sores (occurs within weeks). 

• Diarrhea (occurs within days to weeks). 

• Skin problems (follicular acne, redness, desquammation - peeling of skin). 

• Sensitivity to sunlight. (see skin reactions)

These side effects are less common side effects (occurring in about 10-29%) of patients receiving dactinomycin:

• Loss of appetite 

• Fatigue 

• Darkening of the skin where previous radiation treatment has been given (radiation recall- see skin reaction). 

• Liver problems (hepatotoxicity and elevated liver enzymes) 

• Loss of fertility.  Meaning, your ability to conceive or father a child may be affected by dactinomycin.  Discuss this issue with your health care provider.

There is a slight risk of developing a secondary cancer months to years after taking dactinomycin.  Talk to your doctor about this risk.

Precautions: 

• Before starting dactinomycin treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.). Do not take aspirin, products containing aspirin unless your doctor specifically permits this. 

• Dactinomycin should not be given if you have or have been exposed to chicken pox or if you have recently had shingles. 

• Do not receive any kind of immunization or vaccination without your doctor's approval while taking dactinomycin. 

• Avoid sun exposure.  Wear SPF 15 (or higher) sunblock and protective clothing. 

• Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment.  Pregnancy category C (use in pregnancy only if benefit to mother outweighs risk to fetus). 

• For both men and women: Do not conceive a child (get pregnant) while taking dactinomycin. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy. 

• Do not breast feed while taking this medication.

Mechanism of action: intercalation between guanine-cytosine base pairs

inhibits DNA-dependent RNA synthesis

blocks protein synthesis

Cancerous tumors are characterized by cell division, which is no longer controlled as it is in normal tissue.   "Normal" cells stop dividing when they come into contact with like cells, a mechanism known as contact inhibition.  Cancerous cells lose this ability.  Cancer cells no longer have the normal checks and balances in place that control and limit cell division.  The process of cell division, whether normal or cancerous cells, is through the cell cycle.  The cell cycle goes from the resting phase, through active growing phases, and then to mitosis (division).

The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division.  Usually, the drugs work by damaging the RNA or DNA that tells the cell how to copy itself in division.  If the cells are unable to divide, they die.  The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink.  They also induce cell suicide (self-death or apoptosis).

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific.  Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific.  The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective.  This is why chemotherapy is typically given in cycles.

Chemotherapy is most effective at killing cells that are rapidly dividing.  Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells. The "normal" cells will grow back and be healthy but in the meantime, side effects occur.  The "normal" cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss.  Different drugs may affect different parts of the body.

Chemotherapy (anti-neoplastic drugs) is divided into five classes based on how they work to kill cancer.  Although these drugs are divided into groups, there is some overlap among some of the specific drugs.  The following are the types of chemotherapy:

Further reading

• Antibiotic Classes in 7 minutes

• A Brief Overview of Classes of Antibiotics

•