- Cancer is uncontrolled proliferation and abnormal multiplication of cells within the body.
- A mass of tissue formed as a results of;
- Autonomous and
- Proliferation of cells
The Cell Cycle
- Malignant cells go through normal mitosis but synthesize DNA and divide at a faster rate
- Most chemo drugs exert antineoplastic effects during DNA synthesis (S-phase) or mitosis [Cell Cycle Specific (CCS) drugs].
- Other chemo drugs sterilize tumor cells whether they are cycling or resting in the Go compartment [Cell Cycle Non-Specific (CCNS)]
Possible signs and symptoms
- Abnormal bleeding.
- Prolonged cough.
- Unexplained weight loss.
- Change in bowel movement.
- Weight loss
Types of Cancer
|Types of cancer||Affected area|
|Bladder cancer||Urinary bladder|
|Bone marrow cancer||Shafts of long bones|
Methods of treatment in Cancer
- Chemotherapy: 50 % of the patients can be treated with chemotherapy and the rate is about cure in 15 -20 % of patients
Cancer chemotherapy can be curative…
- Acute Leukemias
- Wilm’s Tumour
- Ewing’s Sarcoma
- Hodgkin’s Disease
- Burkitts lymphoma
- Testicular Teratomas
Pathogenesis of cancer
Strategies of treatment
- Eradication of all neoplastic cells.
- If it is not possible then stop or control the enlarging and spreading of cancer.
- Maintain healthy life thus maintain the disease.
- It has to be treated as a chronic disease, either the neoplastic cell burden is initially reduced.
- By surgery or by radiation.
- Adjuvant chemotherapy:
- Chemotherapy is given after surgery or irradiation to destroy micrometastasis & prevent the development of secondary neoplasm.
- Neo-adjuvant chemotherapy:
- To diminish the volume of large primary neoplasm chemotherapy is given before radiotherapy or surgery.
4. Tumor susceptibility and the growth cycle
Problems associated with chemotherapy
- Prolong administration of an anti-cancer drug may produce resistance because some neoplastic cells (melanoma) resistant to it.
- Multi-drugs resistant
- Transmembrane protein (permeability glycoprotein) is responsible for multi-drug resistance.
- This resistance is due to the ATP-dependent pumping of drugs from the cell in presence of P-glycoprotein.
- Certain high concentration drugs i.e. Verapamil inhibit the pump and thus, interfere with the outflux of anticancer agent.
- Rapidly dividing therapies at killing cancer cells also affect the rapidly expanding normal cells.
Common adverse effect
- Most chemotherapeutic agents have a narrow therapeutic index.
- Nausea & Vomiting
- Bone marrow depression
- Foetal death, teratogenicity
A) Cytotoxic drugs
1. Alkylating agent
- Nitrogen Mustard
- Mechlorethamine (Mustine HCl)
- Alkyl sulfonate
- Carmustine (BCNU),
- Lomustine (CCNU)
- Dacarbazine (DTIC),
2. Platinum coordination complexes
3. Anti métabolites
- Folate antagonist
- Methotrexate (Mtx), Pemetrexed
- Purine antagonist
- 6-Mercaptopurine (6-MP)
- 6-Thioguanine (6-TG)
- Pyrimidine antagonist
- 5-Fluorouracil (5-FU)
4. Microtubule damaging agents
- Vincristine (Oncovin)
5. Topoisomerase-2 inhibitors
6. Topoisomerase-1 inhibitors
- Actinomycin D (Dactinomycin)
- Daunorubicin (Rubidomycin)
- Mitomycin C
- Arsenic trioxide
B. Targeted drugs
Tyrosine kinase inhibitor
2. EGF receptor inhibitor
3. Angiogenesis inhibitor
4. Proteasome inhibitor
5. Unarmed monoclonal antibody
C. Hormonal drugs
- Prednisolone and others
3. Selective estrogen receptor inhibitor
4. Selective estrogen receptor down regulators
7. 5-α reductase inhibitor
8. GnRH analogues
- Hydroxyprogesterone acetate.
Alkylating agent (MOA)
- Alkylating agents irreversibly bind with nucleic acid (DNA) and inhibit cell reproduction.
- The Alkylating agents are produced highly reactive carbonium ions and involved in alkylation.
- After alkylation transfer alkyl groups or substituted alkyl groups to cellular macromolecules by forming covalent bonds.
- That results in DNA is unable to replicate and therefore no protein synthesis occurs.
- The cell synthesis is inhibited.
- First nitrogen mustard.
- Highly reactive and vesicant/irritant drugs.
- Route: only i.v.
- Adverse effects: nausea, vomiting, and hemodynamic changes, Bone marrow depression, aplasia, Menstrual irregularities
- Hematological cancers, lymphomas, solid tumors
- Hodgkins as part of MOPP, CML (Chronic Myelogenous Leukemia), CLL (Chronic lymphocytic leukemia)
- 0.1 mg/kg i.v. daily × 4 days. Repeated at suitable intervals.
- Effective in MULTIPLE MYELOMA
- less alopecia
- Locally less irritant.
- Adverse Effects
- Bone marrow Depression
- Infections , diarrhoea and pancreatitis
- 0.25 mg/kg daily for 4 days every 4-6 weeks
- Most commonly used alkylating agent a prodrug.
- Adverse effect:
- Hemorrhagic cystitis
- nausea & vomiting
- SIADH (Syndrome of inappropriate antidiuretic hormone secretion)
- Hepatic damage
- 2-3 mg/kg/day oral
- 10-15 mg/kg IV every 7-10 days
- It can be administered IV, IM, IP, intrapleurally, Intraarterialy, directly into tumor
- Congener of cyclophosphamide
- Longer half-life than cyclophosphamide
- Less alopecia and less emetogenic than cyclophosphamide
- Can cause hemorrhagic cystitis and severe neurological toxicity
- Used for germ cell testicular tumors and adult sarcomas
- Slowest acting and least toxic alkylating agent
- Main action on lymphoid series produces marked lympholytic action
- Drug of choice for long term maintenance therapy of CLL, chronic lymphatic leukaemia; non-Hodgkin lymphoma and few solid tumours.
- Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance.
- Triethylene phosphoramide
- Does not require to form active intermediate.
- Active intravesicular agent can also be used topically in superficial bladder cancer
- Not well absorbed orally given IV
- High toxicity
- 0.3–0.4 mg/kg i.v. at 1–4 week intervals.
- Depresses bone marrow with selective action on myeloid series
- Primarily used in Chronic Myelogenous leukemia 2-6 mg/day
- Adverse effect:
- Interstitial pulmonary fibrosis
- Venoocclusive disease of liver
- After activation in liver, it acts by methylating DNA and interfering with its function.
- Malignant melanoma
- Adverse effect
- Nausea, vomiting
- 3.5 mg/kg/day i.v. for 10 days, repeat after 4 weeks.
- It is not an alkylating agent but has similar properties.
- After metabolic activation, Procarbazine methylates and depolymerizes DNA causing chromosomal damage.
- Also Inhibition of nucleic acid synthesis.
- Alterative drugs of brain tumor.
- Component of MOPP regimen.
PLATINUM COORDINATION COMPLEXES (Cisplatin)
- Non cell cycle specific killing.
- Administered IV.
- Highly bound to plasma proteins.
- Gets concentration in kidney, intestine, testes.
- Poorly penetrates BBB.
- Slowly excreted in urine.
Mechanism of action
- Testicular cancer (85% – 95 % curative )
- Ovarian cancer
- Other solid tumors: lung, esophagus, gastric
- Adverse effects
- Peripheral neuropathy
- Better tolerated.
- Nephrotoxicity, ototoxicity, neurotoxicity low.
- Less emetogenic.
- But thrombocytopenia and leukopenia may occur.
- Less plasma protein binding.
- primarily in ovarian cancer of epithelial origin
- Squamous cell carcinoma of head and neck
- Folate Antagonists
- Purine Antagonists
- 6 Mercaptopurine, 6 Thioguanine, Azathioprine
- Pyrimidine antagonists
- 5 Fluorouracil, cytarabine, gemcitabine
- Methotrexate inhibits the enzyme dihydrofolate reductase. The conversion of dihydrofolic acid to tetrahydrofolic acid is blocked.
- The inhibition of DHFR can be reversed by an excess of the natural substrate, dihydrofolate (FH2), or by administration of leucovorin (Folinic acid – used as a toxic effect of Methotrexate), which bypasses the blocked enzyme and restore the folate pool.
- Methotrexate is a cell cycle-specific drug, which inhibits DNA replication within the “S” phase of the cell cycle.
- Pralatrexate blocks the enzyme thymidylate synthase as well as DHFR.
- Cytotoxic actions
- Predominant on bone marrow.
- Ulceration of intestinal mucosa.
- Crosses placenta interferes with embryogenesis foetal malformations and death.
- Immunosuppressive action
- Prevents clonal expansion of B & T lymphocytes
- Anti-Inflammatory action
- Interferes with release of inflammatory cytokines IL-2, IL-6,IL-8 & TNF-α , ↓ Rheumatoid.
- Orally absorbed.
- 50% plasma protein-bound.
- Less metabolized and largely excreted unchanged in urine.
- Aspirin and sulfonamides enhance the toxicity of Mtx by decreasing its renal tubular secretion.
- Salicylates, sulfonamides, dicumarol displace it from protein binding sites.
- Megaloblastic anemia
- Thrombocytopenia, leukopenia, aplasia
- Oral, intestinal ulcer , diarrhoea
- Alopecia , liver damage, nephropathy
- Renal impairment.
Treatment of methotrexate toxicity
- Folinic acid (citrovorum factor, N5 Formyl THF).
- IM/IV 8 to 24 hrs. after initiation of methotrexate.
- 120 mg in divided doses in first 24 hrs., then 25 mg oral/IM 6 hourly for next 48 hrs.
- Choriocarcinoma and trophoblast tumor 15 -30 mg/day orally for 5 days.
- Children 2.5 to 15 mg/day.
- Breast, head & neck, bladder, ovarian cancer.
- Immuno-suppressive agent
- Rheumatoid arthritis, resistant asthma.
- Crohn’s disease, Wegener’s granulomatosis.
- Prevention of graft versus host reaction.
- Medical termination of pregnancy.
- 6-MP penetrates the target cells and be converted to nucleotide analog, 6-MP-ribose phosphate also known as TIMP (Thioinosine monophosphate).
- TIMP inhibits the first step of de novo purinebiosynthesis (Phosphoribosyl pyrophosphate).
- TIMP also blocks the formation of adenosine monophosphate and xanthinuric acid from inosinic acid.
- So that TIMP converted to thioguanine triphosphate and thiodeoxyguanine triphosphate. That can be incorporated into RNA and DNA leading to nonfunctional RNA and DNA.
- Oral absorption is unpredictable. Once enters the blood circulation the drug is widely distributed throughout the body except CSF.
- Decrease bioavailability due to fast pass metabolism in the liver.
- In the liver the 6-MP converted to 6-methylmercaptopurine or to thiouric acid (inactive metabolites), this is then catalyzed by xanthine oxidase.
- The drugs and metabolites are excreted through urine.
- Nausea, vomiting
- Hepatotoxicity (jaundice) etc.
- Warfarin, allopurinol
- SMZ/TMP etc.
- It is a pyrimidine analog.
- Consisting of a fluorine atom at position 5 of the uracil ring.
- It is used to treat slow-growing solid tumors (for example colorectal, breast, ovarian, pancreatic, and gastric carcinomas).
- Also effective for superficial basal cell carcinomas on topical application.
Mechanism of action
- 5-FU enters the cell through a carrier-mediated transport system and converted to deoxynucleotide (5-fluorodeoxyuridine monophosphate [5-FdUMP]).
- 5-FdUMP inhibits the enzyme thymidylate synthase, thus conversion of dUMP to dTMP is blocked.
- The synthesis of DNA is decreased due to lake of thymidine, leading to cell death
- 5-FU is given as i.v. because of severe toxicity to the GI tract.
- In case of skin cancer given topically.
- 5-FU is rapidly metabolized in the liver, lung, and kidney. It is eventually converted to fluoro-β-alanine, which is excreted in the urine.
- Elevated levels of dihydropyrimidine dehydrogenase (DPD) can increase the rate of 5-FU catabolism and decrease its bioavailability.
- Patients with DPD deficiency may show pancytopenia, mucositis, and life-threatening diarrhea.
- Severe mucositis (severe inflammation and ulceration of mucous membrane)
- Myelosuppression (bone marrow suppression leads to decrease the production of blood)
- Palmar-plantar erythrodysesthesia (redness, swelling, and pain on the palms and feet)
- Coronary vasospasm (sudden constriction or narrowing of the coronary artery)
- Capecitabine is a novel, oral fluoropyrimidine carbamate.
- It is used in the treatment of colorectal and metastatic breast cancer
- In presence of the enzyme thymidine phosphorylase, Capecitabine hydrolyzed to 5-FU.
- The cytotoxicity activities are same as 5-FU.
- Capecitabine well absorbed orally.
- Extensively metabolized to 5-FU and is eventually biotransformed into fluoro-β-alanine. Metabolites are primarily eliminated in the urine.
- Chest pain
- Warfarin, phenytoin
- Cytarabine is an analog of 2′-deoxycytidine in which the natural ribose residue is replaced by d-arabinose.
- Cytarabine enters the cell by a carrier-mediated process and phosphorylated by deoxycytidine kinase and other nucleotide kinases to cytosine arabinoside triphosphate or ara-CTP.
- Ara-CTP is an effective inhibitor of DNA polymerase.
- Orally effective
- i.v. administration distribute throughout the body but does not penetrate CNS.
- Also, administer the intrathecal route.
- Liposomal preparation is also available. It provides a slow release of the drug into CSF.
- Cytarabine undergoes extensive oxidative deamination in the body to ara-U, a pharmacologically inactive metabolite.
- Both Cytarabine and ara-U are excreted in the urine.
- Nausea, Vomiting
- Neurologic toxicity,
- Conjunctivitis (high dose)
- Digoxin, alkylating agents, methotrexate