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Flashcards in ANTI-CANCERS Deck (93)
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1
Q

INDICATIONS FOR CHEMOTHERAPY:

A

Chemotherapy is presently used in four main clinical settings:

  1. Primary (induction) chemotherapy .
  2. Neoadjuvant chemotherapy .
  3. Adjuvant chemotherapy .
  4. Site-directed chemotherapy.
2
Q

PRIMARY CHEMOTHERAPY

A
  • Chemotherapy administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists.
  • The goals of therapy are to:
  1. Relieve tumor related symptoms.
  2. Improve overall quality of life.
  3. Prolong time to tumor progression.
3
Q

NEOADJUVANT CHEMOTHERAPY

A
  • Chemotherapy is administered before surgery.
  • The goal is to reduce the size of the primary tumor so that surgical resection can then be made easier.
4
Q

ADJUVANT CHEMOTHERAPY

A

Administration of chemotherapy after local treatment modalities (e.g. surgery) has been performed.

Destroys microscopic cells that may be present after local treatment modalities has been done.

• Reduces the incidence of both local and systemic recurrence and to improve the overall survival of patients.

5
Q

SITE-DIRECTED CHEMOTHERAPY

A
  • Direct instillation into sanctuary sites (intrathecal or peritoneal).
  • Regional perfusion of the tumor(e.g. Intra- arterial)
6
Q

TUMOR SUSCEPTIBILITY TO CHEMOTHERAPY

GROWTH FRACTION?

A
  • GROWTH FRACTION = the percentage of actively dividing cells at any given point in time.
  • Malignant neoplasms with high growth fraction (E.g. leukemia and lymphoma) are more sensitive to chemotherapeutic drugs.
  • Low growth fraction tumors (Solid tumor e.g. carcinomas of the colon, lung cancer) are less responsive to chemotherapeutic drugs.
7
Q

TREATMENT PROTOCOLS FOR CHEMOTHERAPY

A

• Combination chemotherapy is the standard approach in the management of many tumors because it:

  1. Provides maximal cell kill within the range of toxicity tolerated by the host for each drug.
  2. Drug combinations are effective against a broader range of cell lines.
  3. Some combinations of anticancer drugs appear to exert

synergistic effect.

  1. May prevent or slow the subsequent development of cellular drug resistance.
8
Q

LOG KILL HYPOTHESIS

A
  • The log kill hypothesis proposes that the action of cytotoxic drugs follows first order kinetics.
  • A given dose of chemotherapy kills a CONSTANT FRACTION of a tumor cell population (rather than a constant number of cells).
  • Repeated doses of chemotherapy -with appropriate frequency- are required to eradicate the tumor cells.
9
Q

CHEMOTHERAPY CHALLENGES:

A
  1. Toxicity of chemotherapy to normal cells.
  • Most traditional chemotherapeutic agents currently in use appear to exert their effect on cell proliferation.
  • Proliferation is a characteristic of many normal cells as well as cancer cells, most chemotherapeutic agents have toxic effects on normal cells, particularly those with rapid rate of turnover, such as bone marrow and mucous membrane cells.
  1. Resistance of tumor cells to chemotherapy.
10
Q

CHEMOTHERAPY TOXICITY:

COMMON ADVERSE EFFECTS

A

1) NAUSEA/VOMITING

–> can be treated with 5HT3 blockers and NK1 inhibitors

2) STOMATITIS –> inflammation of the mucous membranes of the mouth

3) ALOPECIA –> HAIR LOSS

4) MYELOSUPPRESSION

FILGRASTIM is used to treat neutropenia

11
Q

RESISTANCE TO CYTOTOXIC DRUGS

A

PRIMARY RESISTANCE
• No response to the drug on the first exposure.

ACQUIRED RESISTANCE
• Single drug resistance

  • Due to increased expression of one or more genes.
  • Multidrug resistance (MDR)
  • Resistance emerges to several different drugs after _exposure to a single agent.***_

P-glycoprotein (permeability glycoprotein) is the most important efflux pump responsible for multidrug resistance. Hence the other name for this pump is multidrug resistance protein 1 (MDR1)

12
Q

CLASSIFICATION OF ANTI-CANCER DRUGS

A

• Cell cycle-specific drugs:
Antineoplastic drugs that exert their action only on cells traversing the cell cycle.

Cell cycle-nonspecific drugs:

Can kill tumor cells whether they are cycling or resting in the G0 compartment. (Although cycling cells are more sensitive).

  • In general cell cycle-specific drugs are most effective in hematologic malignancies and other tumors in which a large proportion of the cells are proliferating or are in the growth fraction.
  • Cell cycle-nonspecific drugs are useful in low- growth fraction solid tumors as well as in high- growth-fraction tumors.
13
Q

CELL CYCLE SPECIFIC AGENTS:

A

1) ANTIMETABOLITES
2) BLEOMYCIN
3) MICROTUBULE INHIBITORS
4) EPIPODOPHYLLOTOXINS
5) CAMPTOTHECINS

14
Q

CELL CYCLE NON-SPECIFIC AGENTS

A

1) ALKYLATING AGNETS
2) PLATINUM COORDINATION COMPLEXES
3) ANTITUMOR ANTIBIOTICS

15
Q

ANTIMETABOLITES (cell cycle specific agent)

A

1) FOLATE ANALOGS
2) PURINE ANALOGS
3) PYRIMIDINE ANALOGS

16
Q

METHOTREXATE (MTX)

A

ANTI-CANCER ANTIMETABOLITE FOLATE ANTAGONIST

MTX undergoes Intracellular conversion to MTX polyglutamates which bind and inhibit dihydrofolate reductase(DHFR) enzyme.

This results in inhibition of the synthesis of tetrahydrofolate(THF) which is involved in denovo synthesis of:

  1. deoxythymidylate nuclotides → Inhibition DNA synthesis.
  2. Purine nucleotides → Inhibition DNA and RNA synthesis.
17
Q

METHOTREXATE CLINICAL APPLICATIONS

AE:

A

• Breast cancer, head and neck cancer, osteogenic sarcoma, bladder cancer, choriocarcinoma, primary central nervous system lymphoma and non-Hodgkin’s lymphoma.

AE:

  • Stomatitis
  • Mucositis
  • Nausea, vomiting and diarrhea.

• Myelosuppression.

  • *• Pulmonary fibrosis.**
  • *• Hepatotoxicity.**
18
Q

LEUCOVORIN

A

-is folinic acid, is givin WITH methotrexate to avoid adverse effects

–> it provides cells with reduced folate to minimize side effects

19
Q

6-MERCAPTOPURINE

MOA:

A

PURINE ANTAGONIST (ANTIMETABOLITE)

-has a very similar structure to HYPOXANTHINE

Mechanism of action:

Thiol analog of hypoxanthine.

 Converted to the nucleotide 6-MP ribose phosphate (6-MPRP, also known as thio-inosinic acid or TIMP) by the salvage pathway enzyme, HGPRT.

 TIMP inhibits phosphoribosyl pyrophosphate AMIDOTRANSFERASE enzyme which catalyzes the rate limiting step of the de novo purine ring biosynthesis.

 Thio-IMP also blocks formation of AMP and GMP from IMP.

 The monophosphate form is metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA. This leads to dysfunctional DNA and RNA.

20
Q

6-MERCAPTOPURINE

CLINICAL APPLICATIONS

ADVERSE EFFECTS?

A

Clinical applications:

6-MERCAPTOPURINE –> 6 y/o’s get it to help cap off their CHILDHOOD ALL

_***Childhood acute leukemia (ALL).***_

Adverse effects:

  • Nausea, vomiting and diarrhoea.
  • Hepatotoxicity.

• Bone marrow suppression.

21
Q

6-MERCAPTOPURINE

inactivated by what? Why is this a problem?

A

  1. 6-MP is inactivated by xanthine oxidase. This is an important issue because the Purine analog Allopurinol, a potent xanthine oxidase inhibitor, is used in the treatment of acute leukemias to prevent the development of hyperuricemia that often occurs with tumor cell lysis.
    - Because Allopurinol inhibits xanthine oxidase, simultaneous therapy with allopurinol and 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. In this setting, the dose of 6-mercaptopurine must be reduced.

2. The 6-MP is also metabolized by the enzyme thiopurine methyltransferase (TPMT).

–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-MP should be reduced.

22
Q

6-THIOGUANINE

A

PURINE ANTAGONIST (ANTIMETABOLITE)

-converted to the nucleotide TGMP by HGPRT

–> TGMP then

  1. Inhibits the synthesis of the Purine nucleotides (by inhibiting PRPP amidotransferase).
  2. Inhibit the phosphorylation of GMP to GDP by Guanylate kinase enzyme
  3. Can be converted to TGTP and dTGTP which incorporate into RNA and DNA respectively.
23
Q

6-THIOGUANINE

CLINICAL APPLICATIONS

A

6-THIOGUANINE –> 6-T –> ONLY has interactions with the TPMT (has no A in it so has NO interaction with ALLOPURINOL)

-Clinical applications:
Nonlymphocytic leukemias.

  • Adverse effects:
    • Nausea, vomiting and diarrhoea. • Hepatotoxicity.
    • Bone marrow suppression.

NOTE: HAS NO INTERACTION WITH ALLOPURINOL

but DOES get metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring.

–> Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities this why the dose of 6-TG should be reduced.

24
Q

PYRIMIDINE ANALOGUES

A

can only make pyramids out of 5 blocks, not out of 6 or any even number….. therefore 5-FLUOROURACIL (the 6’s are for purines)

will be A BIND to make a pyramid

1) 5-FLUOROURICIL
2) CAPECITABINE
3) GEMCITABINE
4) CYTARABINE

25
Q

5- FLUOROURACIL

MOA

A

PYRIMIDINE ANALOG

  • Is administered intravenously.
  • Given topically for skin cancer.
  • Is mainly catabolized by the enzyme ***_Dihydropyrimidine dehydrogenase (DPD).****_
  • A partial or complete deficiency of the DPD enzyme results in severe toxicity.

MOA:

  1. inhibits THYMIDYLATE SYNTHASE –> decreases DNA synthesis
  2. also gets incorporated into RNA
26
Q

5-FLUOROURACIL

clinical applications

AE

A

AE: 5-FLUOROURACIL –> hands and feet each and 5 fingers or toes therefore it gives you HAND-FOOT SYNDROME

COLON also has only 5 letters in it

• First line drug against COLORECTAL CANCER

It also has activity against a wide variety of solid tumors, including cancers of the breast, stomach, pancreas, esophagus, liver, head and neck, and anus.

Given topically for skin cancer.

AE:

Myelosuppression.

Gastrointestinal toxicity in the form of mucositis and diarrhea.

Neurotoxicity.

Skin toxicity manifested by the hand-foot syndrome.

27
Q

CAPECITABINE

A

PYRIMIDINE ANTAGONIST

CAPE –> 4 limbs + CAPE –> therefore is a 5-FU prodrug. Is a superhero –> goes right to the tumor to get catalyzed for the last step

Orally available prodrug of 5-FU

Activated by a three-steps enzymatic conversion to 5-FU.

The first two steps occur in the liver .

The last step occurs in the tumor and it is catalyzed by the enzyme ***_Thymidine phosphorylase.***_

The expression of thymidine phosphorylase is higher in many solid tumors than in corresponding normal tissue, particularly in breast cancer and colorectal cancer.

28
Q

CAPECITABINE

CLINICAL APPLICATIONS

ADVERSE EFFECTS

A

EXACT SAME AS 5-FU BUT LESS SIDE EFFECTS

• First-line treatment of metastatic colorectal cancer.

• Metastatic breast cancer. (superhero gets all the chicks)

AE:

• Diarrhea

Hand-foot syndrome.

Myelosuppression, nausea, vomiting, and mucositis are also observed with this agent, however their incidence is significantly less than that observed with intravenous 5-FU.

29
Q

DEOXYCYTIDINE ANALOGS

A

1) CYTARABINE
2) GEMCITABINE

30
Q

CYTARABINE

MOA

A

ABC –> Cytarabine BINDS/inhibits to the SITE (cyte) of DNA alpha and beta

• Converted to Cytarabine triphosphate which then:

  1. Competitively inhibits DNA polymerase-α (blockade of DNA synthesis).
  2. Competitively inhibits DNA polymerase-β (blockade of DNA repair).
  3. Incorporated into RNA and DNA. Incorporation into DNA leads to interference with chain elongation and defective ligation of fragments of newly synthesized DNA.
31
Q

CYTARABINE

CLINICAL APPLICATIONS

AE

A

• Its activity is limited exclusively to hematologic malignancies, including

  • acute myelogenous leukemia and
  • non-Hodgkin’s lymphoma.

• Not active against solid tumors.

AE:

Myelosuppression

Mucositis

Nausea

Vomiting

Neurotoxicity (when high-dose therapy is administered).

32
Q

GEMCITABINE

MOA

A

MOA: GEM that BINDS to and INHIBITS DNA in the TRIphosphate form

• Phosphorylated to nucleoside di- and triphosphate, which inhibit DNA synthesis.

This Inhibition is a result of:

  • 1) Inhibition of ribonucleotide reductase by Gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for the synthesis of DNA.
  • 2) Incorporation of Gemcitabine triphosphate into DNA which results in chain termination.
33
Q

GEMCITABINE

clinical applicaitons

AE

A

• Broad-spectrum activity against:

  1. Solid tumors: including Pancreatic cancer, non small cell lung carcinoma, bladder cancer, ovarian cancer, soft tissue and sarcomas.
  2. Hematologic malignancies :( non-Hodgkin’s lymphoma).

:( non-Hodgkin’s lymphoma).

AE:

Renal microangiopathy syndromes, including

1) hemolytic-uremic syndrome and

2) thrombotic thrombocytopenic purpura (rarely).

-can also have ELEVATED LIVER ENZYEMS (AST/ALT)

34
Q

MICROTUBULE INHIBITORS

A

 Microtubules are essential for formation of mitotic spindle.

–> required during MITOSIS

 This class includes:

Vincaalkaloids:

A. Vinblastine.

B. Vincristine.

Taxanes:

A. Paclitaxel.

B. Docetaxel.

35
Q

VINCA-ALKALOIDS

PK + MOA:

A

PK:

  • Metabolized by the liver P450 system.
  • Excreted in feces.
  • Dose modification is required in the setting of liver dysfunction.

MOA:

  • Vinca alkaloids bind to β-tubulin. This disrupts assembly of microtubules.
  • This inhibitory effect results in mitotic arrest in metaphase.
  • Microtubules are essential to many cellular functions such as movement, phagocytosis and axonal transport.

AE: of the Vinca alkaloids such as neurotoxicity may be due to disruption of these functions.

36
Q

VINBLASTINE

A

VINCA-ALKALOID

Clinical applications:

• Hodgkin’s and non-Hodgkin’s lymphomas, breast cancer and germ cell cancer.

Adverse effects:

• Nausea and vomiting.
• Bone marrow suppression.

• Alopecia.

*Potent vesicant, and care must be taken in its administration.

37
Q

VINCRISTINE

A

VINCA ALKALOID

Clinical applications:

1. Hematological malignancies:

• Acute lymphoblastic leukemia, Hodgkin’s and non- Hodgkin’s lymphoma.

_***2. Pediatric tumors:***_

• Rhabdomyosarcoma, neuroblastoma, and Wilms’ tumor.

ADVERSE EFFECTS:

Myelosuppression.

Alopecia.

Syndrome of inappropriate ADH secretion (SIADH).

_Neurotoxicity with peripheral neuropathy.****_

Paralytic ileus.

Optic atrophy.

38
Q

TAXANES

A

MICROTUBULE INHIBITOR

Pharmacokinetics:

  • Metabolized extensively by the liver P450 system and nearly 80% of these drugs is excreted in feces via the hepatobiliary route.
  • Dose reduction is required in patients with liver dysfunction.

MOA:

  • Taxanes bind to the β-tubulin subunit of microtubules at a site distinct from the Vinca alkaloid binding site.
  • Unlike the Vinca alkaloids, _Taxanes ***promote microtubule polymerization and inhibit depolymerization.****_
  • Stabilization of the microtubules in a polymerized state arrests cells in mitosis and eventually leads to the activation of apoptosis.
39
Q

PACLITAXEL

A

MICROTUBULE INHIBITOR: TAXANE

Clinical applications:

Solid tumors including: ovarian advanced breast, lung cancer, head and neck, esophageal, prostate, and bladder cancers and AIDS-related Kaposi’s sarcoma.

Nausea and vomiting.

Hypotension.

Arrhythmias.

Neurotoxicity.

Hypersensitivity reactions.

ABRAXANE -albumin-bound Paclitaxel formulation- is approved for use in metastatic breast cancer. (Better side effect profile).

40
Q

albumin-bound Paclitaxel formulation- is approved for use in metastatic breast cancer. (Better side effect profile).

A

ABRAXANE

41
Q

DOCETAXEL

A

MICROTUBULE INHIBITOR: TAXANE

Clinical applications :

  • Second- line therapy in advanced breast cancer and non-small cell lung cancer.
  • Major activity in head and neck cancer, small cell lung cancer, gastric cancer, advanced platinum- refractory ovarian cancer, and bladder cancer.

AE:

  • Hypersensitivity.
  • ****Profound myelosuppression.**** KNOW THIS
  • Fluid retention:Pre-treatment with ***_Dexamethasone***_ is required to prevent fluid retention.
  • ****Neurotoxicity: _does not cause neuropathy as frequently as Paclitaxel.*********_
42
Q
  1. Etoposide
  2. Teniposide
A

belong to the EPIPODOPHYLLOTOXINS

This class includes:

  1. Etoposide
  2. Teniposide

MOA:

  • Inhibit topoisomerase II, resulting in DNA damage through strand breakage. (prevents re-ligaiton of strand breaks)
  • Block cells in the late S-G2 phase.
43
Q

ETOPOSIDE

+

TENIPOSIDE

clinical applications + AE

A

EPIPODOPHYLLOTOXINS

Clinical Applications:

A) Etoposide is indicated for

1) testicular cancer and
2) small cell lung cancer.

B) Teniposide is indicated for

1) refractory childhood ALL

Adverse effects:

• Nausea and vomiting.

  • Alopecia.
  • Myelosuppression.
44
Q

TOPOTECAN

A

CAMPTOTHECIN

MOA:

They inhibit the activity of topoisomerase I, the key enzyme responsible for cutting and religating single DNA strands. Inhibition of this enzyme results in DNA
damage.

Clinical applications:

  • Second-line therapy for advanced ovarian cancer following initial treatment with platinum-based chemotherapy.
  • Second-line therapy of small cell lung cancer.

PK:

• The main route of elimination is renal excretion and dosage must be adjusted in patients with renal impairment.

Adverse effects:

  • Nausea and vomiting.
  • Myelosuppression.
45
Q

IRINOTECAN

A

CAMPTOTHECIN

  • Pharmacokinetics:
  • Irinotecan is a prodrug converted in the liver to an active metabolite.

• Irinotecan and its metabolites are mainly eliminated in bile and feces, and dose reduction is required in case of liver dysfunction.

Clinical applications:

Metastatic colorectal cancer (combined with 5- FU and Leucovorin).

Adverse effects:

  • Myelosuppression.
  • Diarrhea.
46
Q

ANTITUMOR ANTIBIOTICS

A

This class includes:

  • *1. Bleomycin = cell cycle specific**
  • *2. Anthracyclines = cell cycle NON-SPECIFIC**
  • Doxorubicin
  • Daunorubicin
47
Q

BLEOMYCIN

A

ANTITUMOR ANTIBIOTIC: CELL CYCLE SPECIFIC

-is a cell cycle specific agent acting at G2

  • Bleomycin is a small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule.
  • It acts by binding to DNA, which results in single- and double-strand breaks following free radical formation.
48
Q

BLEOMYCIN

PK

CLINICAL APPLICATIONS

A

ANTITUMOR ANTIBIOTIC: CELL CYCLE SPECIFIC (G2)

Pharmacokinetics:

  • It can be administered subcutaneously, intramuscularly, or intravenously.
  • Elimination of Bleomycin is mainly via renal excretion, and dose modification is recommended in patients with renal dysfunction.

Clinical applications:

  • Hodgkin’s and non-Hodgkin’s lymphomas.
  • Germ cell tumor, head and neck cancer, squamous cell cancer of the skin, cervix and vulva.
49
Q

BLEOMYCIN

AE:

A

Adverse effects:***********
Pulmonary fibrosis
• Skin hyperpigmentation.
• Mucositis
_• *Minimal bone marrow suppression_

50
Q

ANTHRACYCLINES

Which drugs?

MOA

A

Anthracyclines includes:

1) Doxorubicin
2) Daunorubicin

MOA:

  • Binding to cellular membranes to alter fluidity and ions transport.
  • Inhibition of topoisomerase II.
  • High-affinity binding to DNA through intercalation, with consequent blockade of the synthesis of DNA and RNA, and DNA strand breakage.
  • Generation free radicals through an iron- dependent enzyme-mediated reductive process.(cause anthracycline-associated toxicity).
51
Q

ANTHRACYCLINES

AE

A
  • Myelosuppression.
  • Mucositis.
  • Cardiotoxicity (treatment with the iron-chelating agent Dexrazoxane is approved to prevent or reduce anthracycline-induced cardiotoxicity).

***Erythema and desquamation of the skin observed at sites of prior radiation therapy “radiation recall reaction”.***

52
Q

DOXORUBICIN

CLINICAL APPLICATION

A

ANTHRACYCLINES

  • One of the most important anti-cancer drugs in clinical practice.
  • Major clinical activity in cancers of the breast, endometrium, ovary, testicle, thyroid, stomach, bladder, liver, and lung; in soft tissue sarcomas.

Used for several childhood cancers, including neuroblastoma, Ewing’s sarcoma, osteosarcoma, and rhabdomyosarcoma.

Active in hematologic malignancies, including acute lymphoblastic leukemia, multiple myeloma, and lymphomas.

53
Q

DAUNORUBICIN

CLINICAL APPLICATIONS

A

• Used in the treatment of acute myeloid leukemia.

• Limited efficacy against solid tumors.

54
Q

ALKYLATING AGENTS

KINDS?

MOA

A

Alkylating agents are divided into different classes, including:

1. Nitrogen mustards: such as

A. Cyclophosphamide

B. Ifosfamide
C. Mechlorethamine

D. Melphalan

2. Nitrosoureas:
A. Carmustine

B. Lomustine

3. Alkyl sulfonates:

-busulfan

4. Methylhydrazines:

-Procarbazine

5. Triazines:

-dacarbazine (DTIC).

Cell cycle-nonspecific drugs.

Transfer of their alkyl groups (CnH2n+1) to various cellular constituents.

Alkylations of DNA within the nucleus represent the major interactions that lead to cell death.

The major site of alkylation within DNA is the N7 position of guanine.

These interactions can occur on a single strand or on both strands of DNA through cross-linking, as most major alkylating agents are bifunctional, with two reactive groups.

55
Q

ALKYLATING AGENTS

ADVERSE EFFECTS

A
  • Occur primarily in rapidly growing tissues such as bone marrow, gastrointestinal tract and reproductive system.
  • Nausea and vomiting are common. (pre-treatment with 5-HT3 receptor antagonists)

They are potent vesicants and can damage tissues at the site of administration as well as produce systemic toxicity.

Carcinogenic in nature, and there is an increased risk of secondary malignancies, especially acute myelogenous leukemia.

56
Q

CYCLOPHOSPHAMIDE

Clinical applications:

Adverse effects:

A

NITROGEN MUSTARD: ALKYLATING AGENT

Clinical applications:

Cyclophosphamide is one of the most widely used alkylating agents.

Breast cancer, ovarian cancer and soft tissue sarcoma.

Non-Hodgkin’s lymphoma and chronic lymphocytic leukemia.

Neuroblastoma, Wilms’ tumor and rhabdomyosarcoma.

AE:

  • Nausea and vomiting.
  • Bone marrow suppression.
  • Hemorrhagic cystitis(prevented by adequate hydration and parenteral administration of _MESNA***)_
57
Q

CYCLOPHOSPHAMIDE

PK

A

 Pharmacokinetics:

 Can be administered via the oral and intravenous routes with equal clinical efficacy.

 Activated by hepatic microsomal cytochrome P450s- including CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18 and 2C19, with ***_2B6*** displaying the highest 4-hydroxylase activity_- which converts cyclophosphamide to 4 hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are delivered to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms-phosphoramide mustard and acrolein—occurs.

 The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide.

58
Q

CYCLOPHOSPHAMIDE

AE

A

Adverse effects:

1) Nausea and vomiting
2) Bone marrow suppression which leads to pancytpenia

3) Hemorrhagic cystitis:

Acrolein, a metabolite of cyclophosphamide is responsible for the hemorrhagic cystitis caused by therapy with cyclophosphamide. This can be prevented by parenteral administration of ***_Mesna***_, a sulfhydryl compound that reacts with acrolein in the bladder. Also, ample fluid intake is recommended. Vigorous IV hydration is required during high-dose treatment.

59
Q

IFOSFAMIDE

PK

AE:

A

NITROGEN MUSTARD - ALKYLATING AGENT

-MORE POTENT version of cyclophosphamide

Pharmacokinetics:
• A Prodrug administered via IV route.
• Activated in the liver, by cytochrome p450 3A4.

AE:

Nausea and vomiting.

Bone marrow depression.

Alopecia.

_***Nephrotoxicity.***_

Hemorrhagic cystitis (prevented by adequate hydration and parenteral administration of Mesna).

Has virtually the same toxicity profile as cyclophosphamide, although it causes greater

1) platelet suppression,

2) neurotoxicity, and

3) urinary tract toxicity.

60
Q

MECHLORETHAMINE

PK:

A

NITROGEN MUSTARD - ALKYLATING AGENT

Pharmacokinetics:

  • Very unstable. Solutions must be made up just prior to administration.
  • Largely replaced by cyclophosphamide, melphalan and other more stable alkylating agents.
  • Powerful vesicant (given IV only). –> tends to cause BLISTERING
61
Q

MECHLORETHAMINE

Clinical Applications

AE

A

Clinical Applications:

Hodgkin’s lymphoma.

Adverse effects:

  • Severe nausea and vomiting.
  • Severe bone marrow depression.
  • Alopecia.
  • Immunosuppression.
62
Q

MELPHALAN

A

NITROGEN MUSTARD -ALKYLATING AGENT

Clinical applications:

_***• Multiple myeloma. ***_

  • Breast cancer.
  • Ovarian cancer.

Adverse effects:

  • Bone marrow suppression.
  • Nausea, vomiting and diarrhea.

• Oral ulceration.
_• Hepatotoxicity.
• Pulmonaryfibrosis.
_

63
Q

NITROSOUREAS

EXAMPLES

CLINICAL APPLICATIONS

AE

RESISTANCE

A

ALKYLATING AGENT

  1. CARMUSTINE (IV)
  2. LOMUSTINE (ORAL)

Clinical applications:

The nitrosoureas are highly lipid-soluble and are able to readily cross the blood-brain barrier.

1) Brain tumors.

2) Lymphomas.

Adverse effects:

• Myelosuppression.

  • Renal failure.
  • Pulmonary fibrosis.

Resistance:

• Non-cross-resistant with other alkylating agents.

64
Q

BUSULFAN

A

ALKYL SULFONATE

Clinical applications:
• Chronic myelogenous leukemia.

Adverse effects:

  • Nausea and vomiting.
  • Bone marrow suppression.

_• ***Pulmonary fibrosis.***_

65
Q

PROCARBAZINE

A

METHYLHYDRAZINE: AN ALKYLATING AGENT

Clinical applications:
• Hodgkin’s and non-Hodgkin’s lymphoma.

• Brain tumors.

AE:

CNS depression (acute toxicity).

Myelosuppression.

Hypersensitivity reactions.

One metabolite is a weak monoamine oxidase (MAO) inhibitor, and adverse events can occur when procarbazine is given with other MAO inhibitors as well as tyramine-containing foods.

_***Carcinogenic potential is higher***_ than that of most other alkylating agents (increased risk of secondary cancers in the form of acute leukemia).

66
Q

DACARBAZINE

A

TRIAZINE (alkylating agent)

  • Clinical applications:
  • Malignant melanoma, Hodgkin’s lymphoma, soft tissue sarcomas, and neuroblastoma.
  • _***Potent vesicant_ ****(causes blisters) and care must be taken to avoid extravasation during drug administration.

Adverse effects:

  • Myelosuppression.
  • Nausea and vomiting.
67
Q

PLATINUM COORDINATION COMPLEXES

PK

MOA

A

PLATINUM ANOLOGUES =

1) CISPLATIN
2) CARBOPLATIN

PK

• Extensively cleared by the kidneys and excreted in the urine. As a result, dose modification is required in patients with renal dysfunction.

Mechanism of action:

  • Binds DNA through the formation of intrastrand and interstrand cross-links, thereby leading to inhibition of DNA synthesis and function.
  • The primary binding site is the N7 position of guanine. (IE SAME AS ALL OTHER ALKYLATING AGENTS)
68
Q

CISPLATIN

clinical applications

AE

A

PLATINUM COMPOUND: ALKYLATING AGENT

Clinical applications:

• Major antitumor activity in a broad range of solid tumors, including non-small cell and small cell lung cancer, esophageal and gastric cancer, cholangiocarcinoma, head and neck cancer, and genitourinary cancers, ****_particularly testicular, ovarian, and bladder cancer.*****_

AE:

Nausea and vomiting.

Mild to moderate myelosuppression.

Anaphylactic-like reactions.

Peripheral sensory neuropathy.

Ototoxicity.

Nephrotoxicity.

Electrolyte disturbances:

↓ Mg+2, ↓ Ca+2, ↓ K+1and ↓ PO4-3.

69
Q

MANAGEMENT OF CISPLATIN INDUCED NEPHROTOXICITY?

A

PLATINUM COMPOUND: ALKYLATING AGNET

Cisplatin-induced nephrotoxicity has been largely abrogated by adequate pre-treatment hydration and diuresis.

Amifostine is a thiophosphate cytoprotective agent indicated to reduce the cumulative renal toxicity associated with repeated administration of cisplatin.

70
Q

CARBOPLATIN

Clinical Applications

AE

A

PLATINUM COMPOUND: ALKYLATING AGENT

Clinical applications:

• Ovarian cancer, non-small cell and small cell lung cancer, breast cancer, head and neck cancer and bladder cancer.

Adverse effects:

Nausea and vomiting

Myelosuppression.

_****Significantly less nausea, neurotoxicity, ototoxicity and nephrotoxicity (compared to cisplatin).****_

71
Q

HORMONAL AGENTS

3 CLASSES

A

1) GLUCOCORTICOIDS
- PREDNISONE
2) ESTEROGEN INHIBITORS

A) SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERMs):

  1. Tamoxifen
  2. Raloxifene

B) SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDs)

  1. Fulvestrant

C) AROMATASE INHIBITORS:

  1. Anastrozole
  2. Letrozole
  3. Exemestane

3) ANDROGEN INHIBITORS
A. GONADOTROPIN-RELEASING HORMONE ANALOGS

  1. Goserelin
  2. Leuprolide

B. ANDROGEN RECEPTOR BLOCKERS

-Flutamide

72
Q

PREDNISONE

A

GLUCOCORTICOID

Induces lymphocyte apoptosis.

Used against lymphocytes-drived neoplasm such as; acute lymphoblastic leukemia, lymphoma and multiple myeloma.

Effective in the management of autoimmune hemolytic anemia and thrombocytopenia associated with chronic lymphocytic leukemia.

73
Q

ESTROGEN INHIBITORS

CLASSES

A
  1. SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERM)
  2. SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDS)
    3) AROMATASE INHIBITORS
74
Q

SELECTIVE ESTROGEN-RECEPTOR MODULATORS (SERM)

WHAT 2 DRUGS?

A
  • Bind to and activate or block estrogen receptors depending on the target tissue.
  • 1) TAMOXIFEN.

 Has an anti-estrogen effect at the breast.

 _Acts as estrogen receptors agonist at endometrium and bone. –> ***GET ENDOMETRIAL HYPERPLASIA!!!*****_

 Used in the prevention and treatment of breast cancer.

 Adverse effects:

Hot flushes

Nausea and vomiting

Fluid retention

Thromboembolic events

Endometrial hyperplasia(risk of endometrial cancer)

• 2) RALOXIFENE.

Estrogen antagonist at the breast and endometrium (no endometrial hyperplasia).

 Estrogen agonist effect at bone.

 Prevention of postmenopausal osteoporosis

 Prophylaxis of breast cancer in high risk postmenopausal women.

 Can cause thromboembolic events

75
Q

SELECTIVE ESTROGEN-RECEPTOR DOWNREGULATORS (SERDS)

which drug?

A

FULVESTRANT

Pure estrogen receptor antagonist with no agonist activity.

Increases ER degradation.

Reduces the number of ER molecules in cells.

_**Used in Tamoxifen-resistant breast cancer.**_

76
Q

AROMATASE INHIBITORS

A

 Inhibit aromatase enzyme which is required for estrone synthesis from androstenedione.

 Estrone is the primary estrogen in postmenopausal women.

Used as Adjuvant chemotherapy in estrogen receptor positive breast cancer.

KNOW THIS:

A) Anastrozole and Letrozole are NONSTEROIDAL COMPETITIVE inhibitor of aromatase

B) Exemestane is a STEROIDAL and IRREVERSIBLE inhibitor of aromatase.

77
Q

ANDROGEN INHIBITORS

KINDS?

A

1) ANDROGEN RECEPTOR BLOCKERS

EG) FLUTIMIDE

2) GONADOTROPIN-RELEASING HORMONE ANALOGS

EG) 1) Goserelin. 2) Leuprolide.

78
Q

FLUTAMIDE

A
  • Non-steroidal, competitive antagonist at the androgen receptor.
  • Used in the treatment of prostatic carcinoma.
  • Frequently causes mild gynecomastia.
  • Occasionally cause reversible hepatic toxicity.
79
Q

GONADOTROPIN-RELEASING HORMONE ANALOGS

A

1) GOSERELIN 2) LEUPROLIDE

Pulsatile administration stimulates FSH and LH release from anterior pituitary. These gonadotropins stimulate the release of gonadal hormones.

Continuous administration of GnRH analogs produces a biphasic response:

1. initial phase (flare):

 During the first 7–10 days of continuous GnRH analogs administration.

 Characterized by increased concentrations of gonadal hormones production. (INCREASED LH, FSH, + TESTOSTERONE)

 This phase can be effectively counteracted with concurrent administration of

Flutamide for 2- 4 weeks (see below). (PLAY THE FLUTE TO DECREASE YOUR MANLYNESS)

2. Delayed phase: DECREASED LH, FSH, TESTOSTERONE

 Continuous presence of GnRH analogs results in an inhibitory action that manifests as

1) a drop in the concentration of gonadotropins and gonadal steroids (ie, hypogonadotropic hypogonadal state).
2) The inhibitory action is due to a combination of receptor down-regulation and changes in the signaling pathways activated by GnRH.

Continous administration of GnRH analogs is used against PROSTATE CANCER. Can cause Impotence, hot flashes and testicular atrophy.

80
Q

SIGNAL TRANSDUCTION INHIBITORS

A
This class includes:
1. Inhibitors of **_EGFR (ErbB1) and HER2/neu (ErbB2)._**
  1. Inhibitors of BCR-ABL & C-KIT.
  2. Inhibitors of RAS/MAP kinase pathways.
  3. Proteasome Inhibitors.
  4. Angiogenesis Inhibitors.
  • Cancer is driven by genetic and epigenetic alterations, which lead to uncontrolled cell proliferation and tumorigenesis .
  • Many of these alterations involve the cell signaling pathways.
  • Signal transduction (cell signaling) is the transmission of molecular signals from a cell’s exterior to its interior.
  • Signals received by cells must be transmitted effectively into the cell to ensure an appropriate response.
  • This process is initiated by cell-surface receptors.
  • Protein kinases are critical components of signal transduction pathways that regulate cell growth and adaption to the extracellular environment.
  • Protein kinases can be classified into:
  1. Tyrosine kinases.
  2. Serine and Threonine kinases.
  3. kinases with activity toward all three residues.
81
Q

GEFITINIB

A

INHIBITOR OF EGFR TYROSINE KINASE

-used for SMALL CEL LUNG CANCER

82
Q

ERLOTINIB

A

-INHIBITOR OF THE EGFR TYROSINE KINASE

USES:

1) NON-SMALL CELL LUNG CANCER
2) CARCINOMA OF PANCREAS

83
Q

CETUXIMAB

A

MONOCLONAL ANTIBODY VS. EGFR

-USED FOR COLORECTAL CANCER

–> efficacy of cetuximab is restricted to patients with tumors expressing WILD-TYPE KRAS)

-head and neck cancer also

84
Q

LAPATINIB

A

INHIBITOR OF EGFR + ERB-B2

Clinical applications:

1) non-small cell lung cancer

2) CARCINOMA OF PANCREAS

85
Q

TRASTUZUMAB

A

HUMANIZED MONOCLONAL ANTIBODY AGAINST ERbB2 (HER2)

USES:

1) BREAST CANCER WITH HER2 OVEREXPRESSION
2) CARDIOTOXICITY

86
Q

IMATINIB

A

MOA:

Inhibits the of Bcr-Abl tyrosine kinase.

Inhibits c-kit (receptor tyrosine kinase).

CLINICAL APPLICATIONS:

_1) CML****
2) Kit-positive Gastrointestinal stromal tumor
_.****

3) Idiopathic hypereosinophilic syndrome

87
Q

SORAFENIB

A

1) Inhibits the RAF serine/threonine kinase.
2) Inhibits VEGF-R2 and VEGF-R3, PDGFR-β.

USES:

1) RENAL CELL CARCINOMA

88
Q

BORTEZOMIB

A

moa: PROTEASOME INHIBITOR –> Induces growth inhibition and apoptosis of tumor cells.

Clinical applications:

1) MULTIPLE MYELOMA
2) MANTLE CELL LYMPHOMA

89
Q

SUNITINIB

A
  • INHIBITS ANGIOGENESIS
  • Inhibits VEGFR-1, VEGFR-2, and PDGFR

• Clinical Applications:
• Renal cell carcinoma.
• Gastrointestinal stromal tumor.

90
Q

ASPARAGINASE

MOA

CLINICAL APPLICATION

AE

A

 Mechanism of Action:

 Asparaginase (Aka L-asparagine amidohydrolase) _*hydrolyzes circulating L-asparagine to aspartic acid and ammonia*._

 Because tumor cells in ALL lack asparagine synthetase, they require an exogenous source of L-asparagine. Thus, depletion of L-asparagine results in effective inhibition of protein synthesis. In contrast, normal cells can synthesize L-asparagine and thus are less susceptible to the cytotoxic action of asparaginase.

Clinical application:

Childhood acute lymphoblastic leukemia (ALL).

Adverse effects:

 Hypersensitivity.

 Decrease in clotting factors.

 Liver abnormalities.

 Pancreatitis.

 Seizures and coma.

91
Q

HYDROXYUREA

moa

clinical applications

adverse effects

A

Mechanism of Action:

 ***_Inhibits ribonucleotide reductase***_ which converts ribonucleoside diphosphate to deoxyribonucleosides diphosphate

 This leads to depletion of deoxyribonucleosides trisphosphate pool. DNA synthesis is thereby inhibited.

 Kills cells in S phase.

Clinical applications:

 Malignant melanoma

 Chronic myelocytic leukemia

 Ovarian cancer.

 Primary squamous cell carcinomas of the head and neck, excluding the lip.

 Hydroxyurea is also used in the treatment of adult sickle cell disease (increases the level of hemoglobin F).

Adverse effects:

_ Myelosuppression******_

 Nausea, vomiting and diarrhea.

 Skin rash and hyperpigmentation.

 Macrocytosis

92
Q

INTERFERON ALPHA

MOA

CLINICAL APPLICATIONS

AE

A

Mechanism of Action:

 Stimulates natural killer cells to kill the transformed cells

 Increases the expression of HLA molecules on tumor cells

Clinical applications:

 Kaposi sarcoma

 Hairy cell leukemia

 Renal cell carcinoma

 Antiviral activity against HPV (condylomata acuminata), HBV and HCV.

Adverse effects:

 Flu like symptoms

93
Q

CHEMOMAN

A