anti cancer Flashcards

1
Q

what is cancer

A

Cancer cells use the same nutrients and metabolic
process as normal host cells.
- Cancer cells are altered host cells:
shorter cell cycle (accelerated)
excessive proliferation
higher activity of nucleic acid and protein synthesis
altered cell-cell communication
invasive (disrupt normal healthy tissues)
migration to distant sites - metastasis

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2
Q

how do we treat cancer

A

• Surgery
• Radiation – usually followed up with
• Chemotherapy – then this
• Biological – newer Ab therapies

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3
Q

what are the principles of cancer chemo

A

• Causes a lethal cytotoxic event or apoptosis in the
cancer that can arrest the progression of tumor
growth.
• Generally directed toward DNA or against metabolic
sites essential to cell replication (e.g. the availability
purines and pyrimidines required for synthesis of DNA
and RNA).
• Ideally, these anticancer drugs should interfere only
with cellular processes that are unique to malignant
cells.
• Unfortunately, most anticancer drugs do not
specifically recognize neoplastic cells but, rather, affect
both normal and abnormal cells.
• Most all these drugs will have a steep-dose curve for
both therapeutic and toxic effect

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4
Q

what are the goals of chemo

A

– The ultimate goal of chemotherapy is a cure (long-term,
disease-free survival). This requires the eradication of every
neoplastic cell.
– If a cure is not attainable, then the goal becomes control of the
disease (stop the cancer from enlarging and spreading) to
extend survival and maintain the best quality of life.
– Treating cancer as a chronic disease
– In either case the neoplastic cell burden is reduced by surgery
and/or radiation followed by chemotherapy, immunotherapy,
using biological modifiers or using a combination of these
modalities. Figure 37.3
– In advanced stages of cancer, the likelihood of controlling the
cancer is difficult and the goal is palliation (alleviation of
symptoms and avoidance of life-threatening toxicity).

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5
Q

when do we start chemo

A

– Neoplasms are disseminated and are not amenable to surgery.
– Also used as a supplemental treatment to attack micrometastases
following surgery and radiation treatment, (adjuvant
chemotherapy).
– Prior to the surgical procedure in an attempt to shrink the cancer
(neoadjuvant chemotherapy)
– Also given in low doses to assist in prolonging a remission
(maintenance chemotherapy).

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6
Q

what are the chemo regimens

A

• Drug combination is more successful than single drug treatment
in most cancers.
• Cytotoxic agents with different toxicities, and with different
molecular sites and mechanisms of action, are usually combined
at full doses
• This results in higher response rate and/or potentiated cytotoxic
effects and nonoverlapping host toxicities.
• The advantages of combinations:
– Provide maximal cell killing within the range of tolerated
toxicity
– Effective against a broader range of cell lines in the
heterogeneous tumor population
– May delay or prevent the development of resistant cell lines

• Many cancer treatment protocols have been developed and
applicable to a specific neoplastic state.
• e.g. POMP is used for the treatment of acute lymphocytic
leukemia—
• consists of prednisone, oncovin(vincristine), methotrexate, and
purinethol (mercaptopurine).
• Therapy is scheduled approximately 21 days apart to allow
recovery of the patient’s immune system.
• Drugs are usually administered based on body surface area to
tailor the dosage to each patient

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7
Q

when is the tumor most susceptible against chemo

A

The fraction of tumor cells that are in the replicative cycle (“growth fraction”)
influences their susceptibility to anticancer agents.
– Rapidly dividing cells are generally more sensitive to anticancer drugs,
whereas slowly proliferating cells are less sensitive to chemotherapy.
– In general, nonproliferating cells (those in the G0 phase) usually survive
the toxic effects of many of these agents.
A- Cell cycle specificity of drugs:
- Normal and tumor cells go through growth cycle( fig.37.5) but differ in
the number of cells in various stages in the cycle
a. Cell-cycle specific drugs:
- are effective only against replicating cells (that is, those cells that are cycling).
b. Cell-cycle non-specific drugs:
- used for replicating and non-replicating cells but with greater toxicity in
cycling cells

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8
Q

what is the log kill phenomenon

A

• Destruction of cancer cells follows first-order kinetics (a given dose of drug for a
defined time period destroys a constant fraction of cells regardless the absolute
number of cells, this is called LOG KILL or fraction kill).
• For example: A diagnosis of leukemia is generally made when there are about
109
leukemic cells.
• Consequently, if treatment leads to a 99.999% kill, then 0.001% of 109 cells (or
104 cells) would remain. This is defined as a five-log kill (reduction of 105 cells or
100,000-fold reduction). At this point, the patient will become asymptomatic; that
is, the patient is in remission.

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9
Q

what are the pharmacological sanctuaries of chemo

A

Some tumors find sanctuary in tissues such as CNS, where transport constraints
prevent certain anti-cancers from entering.
• Therefore, a patient may require irradiation or intrathecal administration of drugs
to eliminate the tumor at that site.

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10
Q

how does resistance happen against chemo

A

Resistance to chemotherapy:
– Inherited resistance (for example, melanoma is resistant
to most anticancer drugs)
– Acquired resistance by mutation, particularly after
prolonged administration of suboptimal drug doses.
– Minimized by short-term, intensive, intermittent therapy
with combinations of drugs is advised to be taken.
Multidrug resistance:
• Transmembrane P-glycoprotein is
responsible for this ( ATP-dependent
pump of drugs out of the cell
• Cross-resistance following use of
structurally unrelated agents also
occurs
• Note: P-glycoprotein is normally
expressed at low levels in most
tissues , higher levels in kidney, liver
GIT

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11
Q

what are the side effects of chemo

A

• Therapy affects normal cells undergoing rapid proliferation (buccal mucosa, bone
marrow, GI mucosa, and hair).
• a. Common adverse effects:
• Most of chemotherapeutic drugs have a narrow TI
• Severe vomiting (use antiemetic), stomatitis, bone marrow suppression, and alopecia.
• The duration of side effects varies widely (e.g. alopecia is transient, but the cardiac,
pulmonary, and bladder toxicities are irreversible.

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12
Q

give examples on anti metabolites?

A

methotrexate (folate)

5-fluroracil(pyrimidine)

6-mercaptopurine (purine)

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13
Q

give examples in antibiotics used in chemo

A

dactinomycin

daunorubicin

bleomycin

mitomycin C

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14
Q

give examples on alkylating agents

A

mechlorethamine

cyclophosphamide

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15
Q

give examples on microtubular inhibitors

A

1) Vincristine
vinblastine
2) Paclitaxel

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16
Q

give examples on monoclonal antibodies

A

1) Trastuzumab
2) Rituximab

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17
Q

give examples on steroids and their antagonists

A

1) Prednisone
2) Tamoxifen
3) Raloxifene
4)flutamide

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18
Q

what are anti metabolites

A

• Structurally related to normal compounds that
exist within the cell.
• They generally interfere with the availability of
normal purine or pyrimidine nucleotide
precursors, either by:
• inhibiting their synthesis or
• by competing with them in DNA or RNA
synthesis.
• Maximal cytotoxic effects are in S-phase, DNA
replication (cell-cycle specific).

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19
Q

what is the MOA for methotrexate

A

MOA: Structurally related to folic acid and acts as an inhibitor of dihydrofolate
reductase (DHFR)—the enzyme that converts DHF to its active form, tetrahydrofolic acid
(THF). MTX is specific for the S phase of the cell cycle.
• MTX enters the cell by active transport processes that normally mediate the entry of
folate. Figure 37.9
• The inhibition of DHFR can only be reversed by a 1000-fold excess of the natural
substrate, dihydrofolate (DHF) or by administration of leucovorin( folinic acid), which
bypasses the blocked enzyme and replenishes the folate pool.

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20
Q

how is resistance against methotrexate is formed

A

• Non proliferating cells are resistant to MTX
• Amplification (production of additional copies) of the gene that codes for DHFR,
resulting in increased levels of this enzyme.
• The enzyme affinity for MTX is diminished.
• Reduced influx of MTX.

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21
Q

what are the therapeutic uses for methotrexate

A

• MTX is used usually in combination with other drugs
• Effective against :
• acute lymphocytic leukemia, choriocarcinoma,
Burkitt’s lymphoma in children, breast cancer, and
head and neck carcinomas.
• Low-dose MTX is effective as a single agent against
certain inflammatory diseases, such as severe
psoriasis and rheumatoid arthritis as well as Crohn’s
disease.
• All patients receiving MTX require close monitoring
for possible toxic effects.

22
Q

what are the PK for MTX

A

MTX is variably absorbed at low doses from the GIT
• Administered by IM, IV, and intrathecal routes (because MTX does not
penetrate BBB)
• High concentrations of MTX (i.e good distribution) are found in the intestinal
epithelium, liver, skin, and kidney
• High doses of MTX undergo hydroxylation at the 7-position.
• This derivative is much less active, less water soluble and may lead to
crystalluria.
• Therefore, it is important to keep the urine alkaline and the patient well
hydrated to avoid renal toxicity.
• Excretion of the parent drug and the 7-OH metabolite occurs via the urine

23
Q

what are the side effects for MTX

A


Nausea, vomiting, and diarrhea, stomatitis, myelosuppression, erythema, rash,
urticaria, and alopecia.

Some of these effects can be prevented by giving leucovorin which is taken up more
readily by normal cells than by tumor cells. Doses of leucovorin must be kept minimal
to avoid possible interference with the antitumor action of MTX.

Renal damage is a complication of high-dose MTX and its 7-OH metabolite, which can
precipitate in the tubules. Alkalinization of the urine and hydration help to prevent
this problem.

Hepatic cirrhosis after long-term use of MTX .

Neurologic toxicities are associated with intrathecal administration of MTX and
include subacute meningeal irritation, stiff neck, headache, and fever.

24
Q

what is 6-mecraptopurine 6-MP

A

• Thiol analog of hypoxanthine.
• 6-MP is used in the maintenance of
remission in acute lymphoblastic leukemia.
• Acts as a false metabolite and is
incorporated into DNA and RNA to inhibit
their synthesis

25
Q

what is the moa for 6-MP

A

• 6-MP is converted to 6-MP-ribose phosphate
(6-thioinosinic acid, or TIMP) by
hypoxanthine-guanine phosphoribosyl
transferase (HGPRT).
• 1) TIMP can inhibit the first step of de novo
purine- biosynthesis
• 2) TIMP also blocks the formation of AMP
• 3) TIMP is converted to thioguanine
monophosphate (TGMP), which after
phosphorylation to di- and triphosphates can
be incorporated into RNA.
• The deoxyribonucleotide analogs that are
also formed are incorporated into DNA
(nonfunctional RNA and DNA).

26
Q

how is resistance formed against 6-mp

A

• Decreased levels of HGPRT (e.g. Lesch-Nyhan syndrome)
• Increased dephosphorylation, Increased metabolism of the drug to thiouric acid.

27
Q

what are the PK for 6-mp

A

• Absorption by the oral route is erratic and incomplete.
• Widely distributed throughout the body, except for the CSF.
• The bioavailability of 6-MP can be reduced by the first-pass metabolism in the liver
• 6-MP is converted in the liver to 6-methylmercaptopurine derivative or to thiouric
acid (an inactive metabolite) by xanthine oxidase.
• Xanthine oxidase inhibitor, allopurinol, is frequently used to reduce hyperuricemia in
cancer patients receiving chemotherapy. It is important to decrease the dose of
6-MP by 75% in these individuals.
• The parent drug and its metabolites are excreted by the kidney

28
Q

what are the side effects for 6-mp

A

• Bone marrow depression, anorexia, nausea, vomiting, and diarrhea.
• Hepatotoxicity

29
Q

what is 5-fluorouracil 5-fu

A

• 5-FU, a pyrimidine analog, has a stable fluorine atom in
place of a hydrogen atom.

5-FU is used in the treatment of slowly growing solid
tumors (ex. colorectal, breast, ovarian, pancreatic, and
gastric carcinomas).

30
Q

what is the moa of 5-Fu

A

• 5-FU itself is devoid of antineoplastic activity.
• Enters the cell through a carrier-mediated transport and
is converted to deoxynucleotide (5-flurodeoxyuridine
monophosphate (5-FdUMP) which competes with dUMP
for thymidylate synthase.
• 5-FdUMP is trapped with the enzyme and its coenzyme
methylene-THF in a ternary complex that cannot
proceed to release products.

DNA synthesis decreases due to lack of thymidine,
leading to imbalanced cell growth and “thymidine-less
death” of rapidly dividing cells.
• 5-FU is also added to RNA in the form of 5-FUTP.

31
Q

how is resistance formed against 5-fu

A

• Loss of the ability to convert 5-FU into its active form (5-FdUMP)
• Altered or increased thymidylate synthase levels.

32
Q

what are the PKs for 5-fu

A

• Because of its severe toxicity to the GIT, 5-FU is given IV or topically(skin
cancer).
• Penetrates well into all tissues, including the CNS.
• Rapidly metabolized in the liver, lung, and kidney. It is eventually
converted to fluoro-β-alanine, which is removed in the urine, and to CO2
,
which is exhaled.
• The dose of must be adjusted in the case of impaired hepatic function.
Increased rate of 5-FU catabolism through elevated levels of
dihydropyrimidine dehydrogenase (DPD) can decrease the bioavailability
of 5-FU. ( levels differ among individuals)

33
Q

what are the side effects for 5-fu

A

NV, diarrhea, and alopecia, severe ulceration of the oral and GI mucosa,
bone marrow depression (with bolus injection), and anorexia.

34
Q

why do anti biotics have an antitumer effect

A

• Primarily to their interactions with DNA
(intercalation), leading to disruption of DNA
function
• Anthracyclines also are cytotoxic through:
• inhibition of topoisomerases (I and II),
• production of free radicals
• They are cell-cycle non-specific.

35
Q

what are Doxorubicin and daunorubicin

A

• Anthracycline antibiotics.
• Doxorubicin is one of the most important and widely used anticancer drugs.
• Used in combination with other agents for treatment of different types of cancer
• Effective in the S and G2 phases

36
Q

what is the MOA for Doxorubicin and daunorubicin

A

• Intercalation in the DNA thus block DNA and RNA synthesis.
• Inhibition of DNA repair by inhibition of topoisomerase II–catalyzed
breakage/reunion reaction of supercoiled DNA strands causing irreparable breaks.
• Binding to cell membranes: This action alters the function of transport processes
coupled to phosphatidylinositol activation.
• Generation of oxygen radicals which mediate single-strand scission of DNA and
induce cell membrane lipid peroxidation.

37
Q

what are the PK for Doxorubicin and daunorubicin

A

• IV, because they are inactivated in the GI tract.
• Extravasation is a serious problem that can lead to tissue necrosis.
• Widely distributed (but not BBB or testes).
• Undergo extensive hepatic metabolism. The bile is the major route of excretion, and
the drug dose must be modified in patients with impaired hepatic function
• Because of the dark red color of the anthracycline drugs, the veins may become
visible surrounding the site of infusion, and the drugs also impart a red color to the
urine

38
Q

what are the side effects for Doxorubicin and daunorubicin

A

• Irreversible, dose-dependent cardiotoxicity, a result of the generation of free
radicals and lipid peroxidation (heart has low levels of Super oxide dismutase).
• May lead to left ventricular dysfunction and heart failure
• Cardiotoxicity is decreased by using iron-chelator dexrazoxane . Also, a new
liposomal-encapsulated doxorubicin has been reported to be less cardiotoxic than
the usual formulation.
• Others: transient BM suppression, stomatitis, Increased skin pigmentation.
Alopecia is usually severe

39
Q

what is Dactinomycin moa

A

Polypeptide antibiotic used in combination with
surgery and vincristine for the treatment of
Wilms’ tumor (kidney cancer in kids).
• Used in combination with MTX for gestational
choriocarcinoma.

• Intercalates into the minor groove of the double helix between G-C pair of DNA
forming a stable dactinomycin-DNA complex.
• The complex interferes primarily with DNA-dependent RNA polymerase, and at
high doses, it also hinders DNA synthesis.
• The drug also causes single-strand breaks, due to action on topoisomerase II or
by forming free radicals

40
Q

what is the resistance, pk and side effects of Dactinomycin

A

Resistance:
• Increased efflux of the antibiotic
Pharmacokinetics:
• IV, distributes to many tissues (but not CSF)
• Minimally metabolized in the liver
Adverse effects:
• Bone marrow depression, NV, diarrhea,
stomatitis, and alopecia. Extravasation during
injection produces serious problems.

41
Q

what are alkylating agents

A

Exert their cytotoxic effects
by covalently binding to
nucleophilic groups on DNA.
•Do not discriminate between
cycling and resting cells, but
they are most toxic for rapidly
dividing cells (cell-cycle
nonspecific).
•Used in combination with
other agents to treat a wide
variety of cancers.
•All are mutagenic and
carcinogenic ( secondary cancers)

42
Q

what is Mechlorethamine

A

• Was developed as a vesicant (nitrogen mustard)
during World War I. Its ability to cause
lymphocytopenia led to its use in lymphatic
cancers.
• Was used primarily in the treatment of
Hodgkin’s disease

43
Q

what is Mechlorethamine moa

A


Mechlorethamine is transported into the cell,
where the drug forms a reactive intermediate
that alkylates the N7 nitrogen of a guanine
residue in one or both strands of a DNA
molecule “bifunctional agent.”
• This alkylation leads to cross-linkages between
guanine residues in the DNA chains and/or
depurination, thus facilitating DNA strand
breakage.

Alkylation can also cause miscoding mutations

44
Q

what is the resistance, pk and side effects of Mechlorethamine

A

Resistance:
• Decreased permeability of the drug
• Increased conjugation with thiols such as glutathione
• Increased DNA repair

Pharmacokinetics:
• Mechlorethamine is very unstable, and solutions must be made up just
prior to administration.
• Only administered IV.

Adverse effects:
• Severe NV which can be diminished by pretreatment with ondansetron.
• Severe BM depression limits extensive use.
• Latent viral infections (for example, herpes zoster) may appear because of
immunosuppression.
• Extravasation is a serious problem. If it occurs, the area should be
infiltrated with isotonic sodium thiosulfite to inactivate the drug.

45
Q

what are Vincristine (VX) and vinblastine moa

A


VX and VBL are both cell-cycle specific because they block
mitosis in metaphase (M phase).

They bind to the microtubular protein, tubulin, and blocks the
ability of tubulin to polymerize to form microtubules.

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

46
Q

what is the resistance, pk and adverse effects of VX and VBL

A

Resistance:

Enhanced efflux, Alterations in tubulin structure may also affect binding of the vinca
alkaloids.
Pharmacokinetics : I.V leads to rapid cytotoxic effects and cell destruction.

This causes hyperuricemia due to the oxidation of purines that are released from
fragmenting DNA molecules, producing uric acid (ameliorated by administration of the
xanthine oxidase–inhibitor allopurinol).

Vinca alkaloids are concentrated and metabolized in the liver by cytochrome P450. They are
excreted into bile and feces.
Adverse effects:

Phlebitis or cellulitis, if the drugs extravasate during injection

Nausea, vomiting, diarrhea, and alopecia.

VBL is a more potent myelosuppressant than VX, whereas peripheral neuropathy is
associated with VX.

Constipation is more frequently encountered with VX, which can also cause inappropriate
antidiuretic hormone secretion.

47
Q

what is paclitaxel

A

• Known as Taxol. It has good activity against advanced
ovarian cancer and metastatic breast cancer.
MOA:
• Active in the G2
/M phase of the cell cycle.
• Binds reversibly to the β-tubulin subunit, but unlike the
vinca alkaloids, they promote polymerization and
stabilization of the polymer rather than disassembly
• The overly stable microtubules formed are
nonfunctional, and chromosome desegregation does
not occur. This results in death of the cell.
Adverse effects:
• The dose-limiting toxicity is neutropenia. Treatment
with granulocyte colony-stimulating factor can help to
reverse neutropenia.
• Peripheral neuropathy can develop.

Alopecia occurs, but vomiting and diarrhea are
uncommon.

48
Q

why are tumors sensitive for steroids

A

1.
Hormone responsive, in which the tumor regresses (decreases) following
treatment with a specific hormone.
• E.g. Glucocorticoids at higher doses (ex. prednisone) in lymphomas
2.
Hormone dependent, in which removal of a hormonal stimulus causes
tumor regression and can be accomplished by
• Surgery (ex. orchiectomy for patients with advanced prostate cancer) or by
• Drugs (ex. in breast cancer, for which treatment with the
antiestrogen tamoxifen is used to prevent estrogen stimulation of breast
cancer cells).
3.
Both

49
Q

what is prednisone

A


A potent, anti-inflammatory corticosteroid.

Prednisone is employed to induce remission of acute lymphocytic leukemia and in the
treatment of both Hodgkin’s and non-Hodgkin’s lymphomas.
Mechanism of action:

Prednisone is inactive and must first be reduced to prednisolone.

This steroid then binds to a receptor that triggers the production of specific proteins
Resistance: Absence or change in the receptor protein
Pharmacokinetics:

Readily absorbed orally.

Undergoes 11-β-hydroxylation to prednisolone in the liver. Prednisolone is the active drug.

Prednisolone is glucuronidated and excreted into the urine along with the parent compound.
Adverse effects:

Predispose to infection (immunosuppressant action) and to ulcers and pancreatitis.

Hyperglycemia, osteoporosis, and change in mood (euphoria or psychosis).

50
Q

what is Tamoxifen

A


Estrogen antagonist and used for first-line therapy in the treatment of estrogen
receptor–positive breast cancer.
Mechanism of action:

Binds to the estrogen receptor, but the complex is transcriptionally not productive
and fails to induce estrogen-responsive genes, and RNA synthesis does not occur.

Therefore, the growth-promoting effects of estrogen hormone are suppressed.

Tamoxifen is a cell cycle non-specific drug.
Pharmacokinetics:

Effective orally.

Partially metabolized by the liver to active and non-active metabolites.

Unchanged drug and its metabolites are excreted predominantly through the bile
into the feces
Adverse effects:

Hot flashes, NV, skin rash, vaginal bleeding, and discharge (due to some slight
estrogenic activity of the drug and some of its metabolites).

Hypercalcemia requiring cessation of the drug may occur.

51
Q

what is Trastuzumab

A


In metastatic breast cancer, overexpression of human
epidermal growth factor–receptor protein 2 (HER2) is seen in
25 to 30 % of patients.

Trastuzumab a humanized monoclonal antibody, specifically
targets the extracellular domain of the HER2 growth
receptor.

This inhibits the proliferation of cells that overexpress HER2,
thereby decreasing the number of cells in the S-phase.

Usually administered with paclitaxel, can cause regression of
breast cancer and metastases

Pharmacokinetics: administered I.V. and does not penetrate
BBB

Adverse effects: congestive heart failure, infusion-related
fever and chills, NV