Chemotherapy of Malignancy

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CANCER

·         Cancer is the uncontrolled proliferation and abnormal multiplication of cells within the body.

·         A mass of tissue formed as a result of;

o   Abnormal

o   Excessive

o   Uncoordinated

o   Autonomous and

o   purposeless

o   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

  • Lump.
  • Abnormal bleeding.
  • Prolonged cough.
  • Unexplained weight loss.
  • Change in bowel movement.
  • Weight loss

TYPES OF CANCER

Types of cancer

Affected area

Anal cancer

Anus

Breast cancer

Breast

Bladder cancer

Urinary bladder

Bone marrow cancer

Shafts of long bones

Colon cancer

Colon

Cervical cancer

Cervix

Eye cancer

Eye

Wilms tumor

Kidney

Leukemia

Blood

Larynx cancer

Larynx

METHODS OF TREATMENT IN CANCER

  • Surgery
  • Radiotherapy
  • 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
  • Choriocarcinoma
  • Hodgkin’s Disease
  • Lymphosarcoma
  • Burkitt’s lymphoma
  • Testicular Teratomas
  • Seminomas

 

PATHOGENESIS OF CANCER

Strategies of treatment

  1. Goal
    • 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.
    • Education
  1. Adjuvant chemotherapy:
    • Chemotherapy is given after surgery or irradiation to destroy micrometastasis & prevent the development of secondary neoplasm.
  1. 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

  1. Resistance
    • Prolong administration of an anti-cancer drug may produce resistance because some neoplastic cells (melanoma) resistant to it.
  1. 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.
  1. Toxicity
    • 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

·         Stomatitis

·         Alopecia

·         Fetal death, teratogenicity

·         Hyperuricemias

CLASSIFICATION

A.   Cytotoxic drugs

1.      Alkylating agent

·         Nitrogen Mustard

o   Mechlorethamine (Mustine HCl)

o   Cyclophosphamide,

o   Ifosfamide,

o   Chlorambucil,

o   Melphalan

·         Ethylenimine

o   Thio-TEPA

·         Alkyl sulfonate

o   Busulfan

·         Nitrosoureas

o   Carmustine (BCNU),

o   Lomustine (CCNU)

·         Triazine   

o   Dacarbazine (DTIC),

o   Temozolomide

·         Methylhydrazine

o   Procarbazine

2.     Platinum coordination complexes

·         Cisplatin

·         Carboplatin

·         Oxaliplatin

3.     Anti métabolites

·         Folate antagonist

o   Methotrexate (Mtx), Pemetrexed

·         Purine antagonist

o   6-Mercaptopurine (6-MP)

o   6-Thioguanine (6-TG)

o   Azathioprine

o   Fludarabine

·         Pyrimidine antagonist

o   5-Fluorouracil (5-FU)

o   Capecitabine

o   Cytarabine

4.     Microtubule damaging agents

·         Vincristine (Oncovin)

·         Vinblastine

·         Vinorelbine

·         Paclitaxel

·         Docetaxel

·         Estramustine

5.     Topoisomerase-2 inhibitors

·         Etoposide

6.     Topoisomerase-1 inhibitors

·         Topotecan

·         Irinotecan

7.     Antibiotics

·         Actinomycin D (Dactinomycin)

·         Doxorubicin

·         Daunorubicin (Rubidomycin)

·         Epirubicin

·         Mitoxantrone

·         Bleomycin

·         Mitomycin C

8.     Miscellaneous

·         Hydroxyurea

·         L-Asparaginase

·         Tretinoin

·         Arsenic trioxide

B.  Targeted drugs

1.     Tyrosine kinase inhibitor

·         Imatinib

·         Nilotinib

2.     EGF receptor inhibitor

·         Gefitinib

·         Erlotinib

·         Cetuximab

3.     Angiogenesis inhibitor

·         Bevacizumab

·         Sunitinib

4.     Proteasome inhibitor

·         Bortezomib

5.     Unarmed monoclonal antibody

·         Rituximab

·         Trastuzumab

C.  Hormonal drugs

1.     Glucocorticoids

·         Prednisolone and others

2.     Estrogens

·         Fosfestrol

·         Ethinylestradiol

3.     Selective estrogen receptor inhibitor

·         Tamoxifen

·         Toremifene

4.     Selective estrogen receptor down regulators

·         Fulvestrant

5.     Aromatase

·         Letrozole

·         Anastrozole

·         Exemestane

6.     Antiandrogen

·         Flutamide

·         Bicalutamide

7.     5-α reductase inhibitor

·         Finasteride

·         Dutasteride

8.     GnRH analogs

·         Nafarelin

·         Leuprorelin

·         Triptorelin

9.     Progestins

·         Hydroxyprogesterone acetate.

 

ALKYLATING AGENT (MOA)

·         Alkylating agents irreversibly bind with nucleic acid (DNA) and inhibit cell reproduction.

·         The Alkylating agents are produced with 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.

MECHLORETHAMINE (MUSTINE)

·         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

·         Uses:

o   Hematological cancers, lymphomas, solid tumors

o   Hodgkins as part of MOPP, CML (Chronic Myelogenous Leukemia), CLL (Chronic lymphocytic leukemia)

·         Doses:

 

o   0.1 mg/kg i.v. daily × 4 days. Repeated at suitable intervals.

MELPHALAN

  • Effective in MULTIPLE MYELOMA
  •  less alopecia
  • Locally less irritant.

·         Adverse Effects

    • Bone marrow Depression
    • Infections, diarrhea, and pancreatitis

·         Dose

    • 0.25 mg/kg daily for 4 days every 4-6 weeks

CYCLOPHOSPHAMIDE

 

·         The most commonly used alkylating agent a prodrug.

Uses 

Lorem ipsum dolor sit amet, consectetur adipiscing elit. Ut elit tellus, luctus nec ullamcorper mattis, pulvinar dapibus leo.·         Adverse effect:

    • Hemorrhagic cystitis
    • alopecia
    • nausea & vomiting
    • SIADH (Syndrome of inappropriate antidiuretic hormone secretion)
    • Hepatic damage

·         Doses:

    • 2-3 mg/kg/day oral
    • 10-15 mg/kg IV every 7-10 days
    • It can be administered IV, IM, IP, intrapleural, Intraarterialy, directly into the tumor

 

IFOSFAMIDE

  • 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

CHLORAMBUCIL (LEUKERAN)

  • Slowest acting and least toxic alkylating agent
  • The main action on lymphoid series produces marked lymphocytic action
  • Drug of choice for long-term maintenance therapy of CLL, chronic lymphatic leukemia; non-Hodgkin lymphoma, and few solid tumors.
  • Dose: 0.1-0.2 mg/kg daily for 3-6 weeks then 2 mg daily for maintenance.

THIOTEPA

  • Triethylene phosphoramide
  • Does not require to form an active intermediate.
  • An active intravesicular agent can also be used topically in superficial bladder cancer
  • Not well absorbed orally given IV
  • High toxicity

·         Dose

    • 0.3–0.4 mg/kg i.v. at 1–4 week intervals.

BUSULFAN (MYLERAN)

  • Depresses bone marrow with selective action on myeloid series
  • Primarily used in Chronic Myelogenous leukemia 2-6 mg/day

·         Adverse effect:

    • Interstitial pulmonary fibrosis
    • Veno-occlusive disease of the liver
    • Hyperuricaemia
    • Sterility

DACARBAZINE (DTIC)

  • After activation in the liver, it acts by methylating DNA and interfering with its function.

·         Uses

    • Malignant melanoma
    • Hodgkin’s

·         Adverse effect

    • Nausea, vomiting
    • Flu
    • Neuropathy
    • Myelosuppression

·         Dose

    • 3.5 mg/kg/day i.v. for 10 days, repeat after 4 weeks.

PROCARBAZINE

  • 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 the urine.

 Mechanism of action 

·         Uses

    • Testicular cancer (85% – 95 % curative)
    • Ovarian cancer
    • Other solid tumors: lung, esophagus, gastric

·         Adverse effects

    • Emesis
    • Nephrotoxicity
    • Peripheral neuropathy
    • Ototoxicity

CARBOPLATIN

  • Better tolerated.
  • Nephrotoxicity, ototoxicity, neurotoxicity low.
  • Less emetogenic.
  • But thrombocytopenia and leukopenia may occur.
  • Less plasma protein binding.

·         Use:

    • primarily in ovarian cancer of epithelial origin
    • Squamous cell carcinoma of head and neck

ANTIMETABOLITES

·         Folate Antagonists

o   Methotrexate

·         Purine Antagonists

o   6 Mercaptopurine, 6 Thioguanine, Azathioprine

·         Pyrimidine antagonists

o   5 Fluorouracil, cytarabine, gemcitabine

METHOTREXATE (MOA)

·         Methotrexate inhibits the enzyme dihydrofolate reductase. The conversion of dihydrofolic acid to tetrahydrofolic acid is blocked.

·         The inhibition of DHFR can be reversed by the 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.

Pharmacological actions

·         Cytotoxic actions

o   Predominant on bone marrow.

o   Ulceration of intestinal mucosa.

o   Crosses placenta interferes with embryogenesis foetal malformations and death.

·         Immunosuppressive action

o   Prevents clonal expansion of B & T lymphocytes

·         Anti-Inflammatory action

o   Interferes with the release of inflammatory cytokines IL-2, IL-6, IL-8 & TNF-α, ↓ Rheumatoid.

Pharmacokinetics

·         Orally absorbed.

·         50% plasma protein-bound.

·         Less metabolized and largely excreted unchanged in the urine.

·         Aspirin and sulfonamides enhance the toxicity of Mtx by decreasing its renal tubular secretion.

·         Salicylates, sulfonamides, dicumarol displace it from protein binding sites.

Adverse effects

·         Megaloblastic anemia

·         Thrombocytopenia, leukopenia, aplasia

·         Oral, intestinal ulcer, diarrhea

·         Alopecia, liver damage, nephropathy

Contraindication

·         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.

Uses

·         Antineoplastic

o   Choriocarcinoma and trophoblast tumor 15 -30 mg/day orally for 5 days.

o   Children 2.5 to 15 mg/day.

o   Breast, head & neck, bladder, ovarian cancer.

·         Immuno-suppressive agent

o   Rheumatoid arthritis, resistant asthma.

o   Crohn’s disease, Wegener’s granulomatosis.

o   Prevention of graft versus host reaction.

·         Psoriasis

o   Medical termination of pregnancy.

PURINE ANTAGONIST

6-MERCAPTOPURINE

·         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 purine biosynthesis (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. 

Pharmacokinetics

·         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 is converted to 6-methylmercaptopurine or thiouric acid (inactive metabolites), this is then catalyzed by xanthine oxidase.

·         The drugs and metabolites are excreted through urine.

Adverse effects

·         Nausea, vomiting

·         Rashes

·         Anorexia

·         Myelosuppression

·         Hepatotoxicity (jaundice) etc.

Interaction

·         Warfarin, allopurinol

·         SMZ/TMP etc.

 

PYRIMIDINE ANTAGONIST 

5-FLUOROURACIL

  • 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 is 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

Pharmacokinetics

  • 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.

Adverse effects

  • Diarrhea
  • Alopecia
  • Severe mucositis (severe inflammation and ulceration of mucous membrane)
  • Myelosuppression (bone marrow suppression leads to a decrease in 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)

Interaction

  • Methotrexate

CAPECITABINE

  • 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 the 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.

Adverse effects

  • Diarrhea
  • Mucositis
  • Myelosuppression
  • Chest pain

Interaction

  • Warfarin, phenytoin

CYTARABINE

  • 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.

Pharmacokinetics

  • 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.

Adverse effects

  • Nausea, Vomiting
  • Diarrhea
  • Myelosuppression,
  • Hepatotoxicity
  • Neurologic toxicity,
  • Conjunctivitis (high dose)

Interaction

 

  • Digoxin, alkylating agents, methotrexate

1 thought on “Chemotherapy of Malignancy”

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