WordPress Data Table

Classification On The Basis Of Their Effect On The Cell Cycle

Non-Cell Phase Specific Agents

• Exert their cytotoxic effect throughout the cell cycle
• Cell killing is proportional to the dose

Alkylating agents

• Prodrugs transformed to positive ions form covalent bonds with electron-rich sites (DNA, amino acids) breaks in the DNA strand
• E.g: Nitrogen mustards, cyclophosphamide, cisplatin, carboplatin

Antitumor antibiotics

• Most act by either alkylation or intercalation (insertion of a drug molecule between two strands of DNA) and interference with topoisomerase activity.
• E.g: Doxorubicin., daunorubicin, bleomycin

Cell Phase Specific Agents

 

• Nitrosureas:Carmustine (BCNU}i Lomustine (CCNU)
• !Mechanism Of Action:
• Alkylate DNA (through chloroethyl moiety) and carbamoylation of proteins via the isocyanate (O=C=N-R) formed during
• Indication:
• Brain neoplasms
• !Multiple myeloma
• Hodgkin’s disease, non-Hodgkin’s lymphoma
• carcinomas of the gastrointestinal tract..

• Dosage and Administration:
• i. Carmustine-lV dosing
• Lomustine-Orally on an empty stomach every 6 weeks.
• Toxicities:
• Dose limiting myelosuppression (DELAYED) Nadir in approximately 4 weeks
• Additional toxicities include: Severe nausea and vomiting, and pulmonary toxicity

 

• C-Ethylenimines {Thiotepa, Thioplex®)
• Mechanism of Action: Poly functional alkylating agent in which three membered ring metaboli’zes to ethylenimine
• Indication
• Leukemia& Hodgki’n’s dise-ase
• Breast, ovarian, and bladder
• May be used as part of bonemarrow preparative regimens.

Toxicities: Alkylating agent toxicties; When used at high doses for bone marrow preparative regimens, care must be taken due to exc,retion in sweat (baths 3-4 times dai’ly, no tight clothes, etc) to prevent skin breakdown.

 

• D-Alkyl sulfonates,(Busulfan, Myleran)
• 1Mechanism of Action: Cleavage of the alkyl-oxygen bond produces an electrophilic butyl compound that forms crosslinks with
• Indication: chronic myelogenous leukemia and as part of bone marrow preparative
• Dosage and Administration: Oral dosing based on based on white blood counts

 

• Toxicities:
• Pulmonary toxicity
• veno-occlusive disease
• gynecomastia
• skin pigmentati
• .B: When used at high doses for bone marrow preparative regimens phenytoin prophylaxis needed;

 

• E-Triazenes (Dacarbazine, DTIC-DOME; Temozolamide, Temodar®)
• Mechanism of Action: Dacarbazine is a prodrug activated by the cytochrome p4Sq sy t m or photodec mposition forming a methylcarbonium ion (N=N+CH3J that mh1b1ts DNA synthesis.
• Temozolamide is the oral equivalent that is spontaneously converted to the active
• Indication: Melanoma, lymphoma, glioma, sarcoma
• Dosage and Administration Dacarbazine is IV and temozolomide is oral
• Toxicities:
• Severe nausea and vomiting
• Additional toxicities include: Increased liver enzymes, flu-like syndrome, pain at injection site

 

• F-Platinum analogues (Cisplatin, carboplatin, oxaliplatin)
• Mechanis_m of Action: Alkylat_ing-like agents which form a reactive electroph1le that covalently binds to D
• Indication: Effective for the treatment of lung, testicular, bladder, breast, ovarian, colorectal, head and neck, and gastric carcinomas.
• Dosage and Administration:
• Cisplatin:
• (a) V_ig9rous_hydration with adequate urine flow rate required for adm1n1strat
• (b) Prehydration with 1 L of NS+ 20 mEq KCI & 8mEq Mg SO4 over 1 2 hours to obtain a urine flow rate of> l00ml/hour. Post hydration consists of the same IV

 

• Carboplatin: Using the Calvert method:
• Dose (mg)= Target AUC x (CrCI + 25)llltarget AUC is 4-8
• Toxicities:
• Cisplatin
• (a) Dose limiting nausea and vomiting (acute and delayed)
• (b) Additional toxicities incllude: Nephrotoxicity resulting in increased serum creatinine,hypomagnesemia, and hypokalemia. Myelosuppression, ototoxicity, and peripheral neuropathies

 

• Carboplatin
• (a) Dose limiting myelosuppression (thrombocytopenia).
• (b) Decreased incidence of nephrotoxicity, ototoxicity, nausea and vom

 

• Oxaliplatin
• (a) Cumulative peripheral neuropathy
• Acute (within the first two days), reversible (resolves within 14 days), primarily peripheral symptoms that are often exacerbated by cold
• Persistent (>14 days) that often interferes with daily activities such as writing, buttoning1  and swallowing;  symptoms may improve upon treatment discontinuation

 

• (b) Minimal nephrotoxicity and ototoxicity

 

 

 

 

 

 

 

 

OXALI PLATI N

 

 

Peripheral sensory neuropathy

 

• cumulative, dose-related and usually reversible a few months after stopping treatment. Symptoms include sensory ataxia and dysesthesia of the limbs, mouth, throat and larynx, and may be exacerbated by exposure to cold (eg, touching cold surface, drinking cold liquid). The inci’dence of grade 2 neuropathy is 10% after 3 treatment cycles and SO% after 10 Grade 3 neuropathy occurs in 10% after 9 cycles and SO% after 14 cycles, is reversible in 74% of the cases, and begins to recover after 13 weeks. Paresthesia interfering with function (eg,  buttoning clothing, holding objects, writing) is seen in 16%,of patients after 4 months of treatment and rarely leads to oxaliplatin withdrawal.Unlike cisplatin, oxaliplatin neuropathy is related to injury to small rather than large sensory fibres.

 

• Gabapentin PO 100 mg twice daily, with increments of 100 mg PO daily as needed, may be effective in some patients to reduce oxaliplatin neuropathy,. while carbamazepine does not appear to be Other agents used with some success include alpha-lipoic acid 11v 600 mg weekly for 3-5 weeks, then followed by oral 600 mg three times daily

 

• Management of extravasation: Extravasation of o.xaliplatin may sometimes cause severe local inflammation and potentially tissue The optimal nonpharmacological management of oxaliplatin extravasation is unclear. Howev,er, it has been suggested that warm compresses may be pr,eferred over cool compresses

 

PREPARED ONLY IN 5% GLUCOSE ADMINISTERED OVER 2 HOURS.

 

 

 

 

 

 

 

 

 Dosagein renal failure:

 

CrCl(mUmin) –

Serum Creatinine (µmolfl)

 

 

 

 

Dosage in hepatic failure

 

 

Dosage in dialysis:

where= 1.04 for emalesand 1.23formales

 

noadjustmentrequiredfor mildtomoderateliverdysfunction⁶; no infom1·aon oundregarding severe hepaticinsufficiency

 

no informa onfound

 

• Caution:
• Administer with caution to individuals with pre..existing renal impairment, myelosuppression, or hearing impairment. • Hydration is required to minimize nephrotoxicity. The manufacturer recommends pre­ treatment hydration with 1 or 2 L of fluid infused 8-12 hours prior to a cisplatin dose. Hydration with NS, hypertonic saline infusion, and mannitol, or furosemide-induced diuresis is used to effectively decrease·cisplatin­ induced nephrotoxicity.Lower doses of cisplatin are given with less intensi·ve hydration. For example, patients receiving doses of 35 mg/m2 have been pre-treated with 500 mL NS over 1 hour, with no post-hydration. Patients receiving doses of 25 mg/m2 have been pre-treated with vigorous oral hydration (e.g., 600-900 ml) the morning of treatment and 8 glasses (e.g., 2000 ml/day) daily for a few days following treatment

 

• Electrolyte disturbances can be serious and mainly includes hypomagnesemia, hypocalcemia and hypokalemia. Hypophosphatemia and hyponatremia have occurred in some patients receiving cisplatin combination 2 These effects are due to renal tubular damage. Cisplatin greatly increases the urinary excretion of magnesium and calcium; increased excretion of potassium, zinc, copper and amino acids also occurs. Hypomagnesemia and or hypocalcemia may become symptomatic, with muscle irritability or cramps, clonus, tremor, carp pedal spasm and/or tetany. Children may be at greater risk for developing hypomagnesemia.

 

 

 

Hydration protocol for adults

 

 

 

 

Cisptatin (mglm )	Hydration		Elctrol, Addi	Comm–nts
> o	40 0 m	S over4h	KCl2m0 Eq MgQ,1g	1inpaijentor meoicaldaycare unit admision to monitorunn o I ut
60 0	20 0 mlt S over2h		KCl20mEq M -0 1 g Mann
	10 0 m	over1 h	KCI10 M    0.51	includesregimenswi  ci p1         tin dministereodvermulti I da
0	50 ml	over30 min	includs regimenswilli ci platin
			administer a overmulopl day,

 

 

 

 

 

Dosage in renal failure

Calculated creatinine clearance

=

N* x {140 – Age) x weight in kg Serum Creatinine in µmol/L

* For males N=l.23; for females N=l.04

Dosage in hepaticfailure:

no adjustment required Dosage in dialysis:

re.movable by dialysis, but  only within 3 h of administration

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Carhop

 

 

 

 

 

 

 

 

 

 

 

• Cycle Length:
• Intravenous: 2..4 weeks: AUC-based carboplatin dose IV for one dose on day 1
• Calculate carboplatin dose with Calvert formula
• Dose (mg) = AUC*(crcl + 25 )

 

 

 

 

 

 

 

 

 

 

 

 

58

 

 

 

 

 

 

 

 

 

 

 

Dosage   renal   Jure:               adjuslmen r

• ed

A-based dosr g(mglm·) 1s used;

 

is sugges ed:

 

		250
0-19		150
().9		00

 

cula ed cre·arne cleara               x11  0-Age} xweig  in  g

rum crea inlfl (µmolll)

re = 1.    forfema   and .   or m es

 

• Dosage in hepatic failure: no adjustment required
• Dosage in dialysis: hemodialysis: [1] supplement with 50% of the dose after dialysis.
• In dialysis-dependent chronic renal failure, a fixed dose
• of 100 mg (previous platinum treatment) or 150 mg (no
• previous platinum treatment) may be used, with dialysis performed 24 h after carboplatin administrati

 

DR/HEBA LOTFY BCPS,MSC,PHARMD, CPHQ

Chemotherapy Classification

LEC 4

 

Cancertherapeutic groups

 

 

 

 

• ALKYLATING AGENTS
• 1-Nitrogen mustards

 

• Ethylenimines 3-Nitrosoureas

 

• 4-Alkyl sulfonates ENZYME INHIBITORS

• Triazenes 6-Platinum analogues

 

A-TOPOISOMERSE II INHIBITORS { 1-Anthracyclines          2-Epipodophyllotoxins)

B-TOPOISOMERSE I INHIBITORS        { 1-Camptothecins)

3.ANTIMICROTUBULES      { 1-Vinca alkaloids   11-Taxanes                                 111-Epothilones) 4.ANTIMETABOLITES

1-Folate antagonists

II-Purine analogues

Ill-Pyrimidine analogues S.HORMONAL AGENTS 6.TARGETED THERAPIES

7.MISCE LANEOUS AGENTS

 

2.ENZYME INHIBITORS

A-TOPOISOMERSE II INHIBITORS

 

 

• 1–Anthracyclines
• Daunorubicin hydrochloride (Cerubidine®)
• Doxorubicin hydrochloride (Adriamycin®)
• ldarubicin (ldamycin®)
• Epirubicin (Ellence®)

 

 

• 2-Epipodophyllotoxins
• Etoposide (VP-16, Vepesid®)
• Tenoposide (VM-26, Vumon®)

 

3

• 3–Mitoxantrone (Novantrone®)

 

B-TOPOISOMERSE I INHIBITORS

 

 

• 1–Camptothecins
• lrinotecan (Camptosar®)
• Topotecan (Hycamtin®)

 

 

(A)Type I                                                           )Typell

 

11. ENZYMEINHIBITORS

A-TOPOISOMERSE II INHIBITORS

 

•  
• A. Anthracyclines (Daunorubicin, Doxorubicin, ldarubicin, Epirubicin)
• Mechanism of Action:
• I-The anthracyclines induce formation of covalent topoisomerase II-DNA complexes prevents the religation of DNA during DNA replication DNA strand
• II- intercalations between base pairs in the DNA are formed causing additional DNA
• 111-Anthracyclines are also metabolized in the liver to form oxygen free radicals that add to the cytotoxicity, as well as, the toxicity of these

 

• Indication:

 

 

• Solid tumors treatment: treatment of breast, ovary, endometrial, bladder, and thyroid carcinomas.
• used in several different combinations for the treatment of lymphomas and Hodgkin’s disease

 

• .Dosage and Administration:
• Dose reductions required in patients with hepatic impairment.
• Decrease dose by 50% if bilirubin levels 2-3.0 mg/dl
• Decrease by 75% for bilirubin > 3.0 mg/dl
• Do not give if bilirubin >5.0 mg/dl

 

 

• All agents are potent vesicants and require immediate medical attention if extravasation occurs.
• Apply cold ice pack
• Evaluate for antidote use (99% DMSO 1-2 ml applied to site every 6 hours for 7-14 days) or dexrazoxane IV (Totect®)

 

 

• Toxicities:
• Dose limiting myelosuppression- primarily leukopenia
• Chronic cardiomyopathies occur with all this agents
• All patients should have a baseline MUGA done to evaluate potential cardiotoxicity

 

 

• Risk of cardiac toxicity increases with cumulative
• iv. Additional toxicities include: dose dependent nausea and vomiting,
• Patient Issues:
• Doxorubicin will cause red discoloration of the urine and requires patient education.

 

B–Epipodophyllotoxins (Etoposide, VP–16)

 

• Mechanism of Action: Forms a complex with topoisomerase II forming single stranded DNA
• Indication: Effective for the treatment of testicular, ovarian, lymphomas , small-cell lung cancer, and leukemia’s.
• Dosage and Administration:
• IV or oral. IV infusion should be infused over 30-60 minutes to avoid hypotension.
• IV solution should be diluted to a concentration < 0.4mg/ml
• Oral dose is 2x greater than the IV.
• Toxicities: Dose limiting myelosuppression- primarily Additional toxicities include:
• Nausea and vomiting (with oral dosing), alopecia

 

 

 

 

 

 

 

 

• Mitoxantrone (Novantrone)
• Mechanism of Action: Similar to the anthracyclines
• I- formation of covalent topoisomerase II-DNA complexes
• II- lntercalations between base pairs in the DNA are formed causing additional DNA

 

• NB:
• Mitoxantrone does not form oxygen free radicals; and therefore less cardiotoxicity then traditional

 

 

 

 

 

 

 

 

• Indication:
• Effective for the treatment of breast cancer, as well as being used in several different combinations for the treatment of lymphomas and Hodgkin’s
• Toxicities: Dose limiting
• Additional toxicities include: Nausea and vomiting, alopecia,and cardiac
• Patients’ urine may turn blue for 24-48 hours after

 

 

 

 

 

 

 

 

 

 

 

 

 

It

 

 

 

 

 

 

 

 

• . B-TOPOISOMERSE I INHIBITORS
• Camptothecins
• Mechanism of Action: Inhibits the enzyme topoisomerase I resulting in the stabilization of the “cleavable complexes” reversible single stranded DNA
• Topotecan (Hycamtin)
• (a) Indication: FDA approved for the treatment of ovarian cancer.
• (b) Toxicities: Dose limiting leukopenia and Additional toxicities include:
• Nausea and vomiting, alopecia, and increased liver enzymes

 

 

 

 

 

 

 

 

• lrinotecan (Camptosar)
• (a) Indication: FDA approved for the treatment of colorectal and rectal
• (b) Toxicities:
• (c) Dose limiting
• (i) Both early and late
• (ii) Treat early diarrhea with
• (iii) Late diarrhea treated with loperamide

 

 

 

 

 

 

 

 

 

 

 

n

 

. Early onset diarrhea occurs during or within 24 hours of administration of irinotecan. It is usually transient and only infrequently severe. Early onset diarrhea is thought to be part of a cholinergic syndrome. It may be accompanied by other cholinergic symptoms such as rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping. The cholinergic syndrome is more likely to occur at higher irinotecan dose levels and associated with the onset of peak irinotecan plasma levels. Thus, infusing irinotecan over less than 90 minutes may increase the likelihood of the cholinergic syndrome. Early onset diarrhea and cholinergic symptoms are treated with atropine 0.3 – 0.6 mg IV or SC as needed, repeated up to a maximum dose of 1.2 mg. Blood pressure and heart rate should be monitored during atropine therapy. Prophylactic atropine may be required for subsequent treatments.

 

 

 

IV

 

Late onset diarrhea:

This occurs more than 24 hours after administration of irinotecan and can be prolonged,

leading to potentially life-threatening dehydration and electrolyte

imbalance. The median duration of diarrhea for the one-weekly schedule was 3 days, with severe diarrhea (grades 3-4) lasting for 7 days.

Management of  diarrhea should include prompt treatment with high dose loperamide. Patients with severe diarrhea should be carefully monitored for dehydration and given fluid and electrolyte replacement as needed

 

. Premedication with loperamide  prior to  irinotecan treatment is not required. However, patients should be instructed to have loperamide on hand and start the following treatment at the first poorly formed or loose stool, or earliest onset of more frequent bowel movement than usual (NB, loperamide dose used is higher than recommended by the manufacturer):

o loperamide 4 mg immediately

o then 2 mg every 2 hours until diarrhea-free for 12 hours

o may take 4 mg every 4 hours at night.

An alternative regimen of loperamide 4 mg every 3 hours plus diphenhydramine 25 mg every 6 hours has also been used in a limited number of patients. Laxatives may increase the risk of severe diarrheal and patients should be counselled about laxative use during irinotecan treatment.

 

3.   ANTIMICROTU BULES

 

• 1-Vinca alkaloids
• Vinblastine (Velban®)
• Vincristine (Oncovin®)
• Vinorelbine (Navelbine®)

 

• 11-Taxanes
• Paclitaxel (Taxol111,Abraxane®)
• Docetaxel (Taxotere®)
• Cabazitaxel (Jevtana®)

 

• 111-Epothilones (lxabepilone-lxempra®)

20

• Miscellaneous (Eribulin Mesylate–Halaven)

 

. ANTIMICROTUBULES

 

 

• A. Vinca alkaloids:
• Vinblastine, vincristine, vinorelbine are plant products derived form the periwinkle plant.
• Mechanism of Action: vinca alkaloids bind to tubulin inhibiting its polymerization .No formation of the mitotic spindle during the mitosis inhibit cell division in the M phase of the cell

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

“

 

 

 

 

 

 

 

 

• Indication:
• Vinblastine is part of a curative regimen for testicular cancer and Hodgkin’s disease which vincristine is part of curative regimen for non-Hodgkin’s and Hodgkin’s disease .
• Vinorelbine’s main use is in non-small cell lung
• Agents are also used in the treatment of AML, ALL, breast cancer, and bladder cancer.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

H

 

 

 

 

 

 

 

 

 

• Dosage and Administration
• Agents undergo biliary excretion, require adjustments for hepatic impairment.
• 50% Dose reduction for bilirubin > 1.Smg/dl, 75% reduction for bilirubin > 3.0mg/dl; do not give if bilirubin >5.0 mg/dl
• Agents are potent vesicants, apply warm pack and administer hyaluronidase 1ml as an antidote.
• iv. In general, the maximum dose of vincristine is 2mg weekly

 

 

 

 

 

 

 

 

• Toxicities:
• Vinblastine and Vinorelbine
• (a) Dose limiting leukopenia, and thrombocytopenia
• (b) Additional toxicities include: Neurologic toxicity, constipation, abdominal cramps (much less than vincristine)
• Vincristine
• (a) Dose-limiting neurologic toxicity, constipation, and paralytic ileus
• (b) Rarely causes bone marrow suppression and SIADH

 

 

 

 

 

 

 

 

• B. Taxanes
• Mechanism of Action: Similar to the vinca alkaloids the taxanes work in the M phase of the cell cycle.
• Taxanes bind preferentially to the microtubules shifting the microtubules towards polymerization Once the microtubules are polymerized the taxanes then stabilize against
• Indication: Treatment of breast, ovarian, and lung cancer

 

 

 

 

 

 

 

 

• Dosage and Administration
• Paclitaxel (Taxol)
• (a) 135-175mg/m2 IV infusion DSW or NS every 3 weeks.
• (b) Dosing adjustments or holding dose required for liver
• (c) Administer prior to cisplatin or carboplatin when used in combination regimens to decrease myelosuppression.
• (d) Available in a new formation (Abraxane®) which does not contain cremaphor and has less allergic reactions

 

 

 

 

 

 

 

 

• Adverse effects:
• (a) Dose limiting leucopenia
• (b) Additional toxicities: Hypersensitivity reactions, alopecia,cardiac toxicity, peripheral neuropathies, and mucositis

 

 

 

 

 

 

 

 

• Docetaxel (Taxotere)
• (a) Contraindicated in severe hepatic impairment
• Adverse effects: Dose limiting leukopenia.
• Additional toxicities include: Peripheral edema, alopecia, peripheral neuropathies, and hypersensitivity reactions

 

 

 

 

 

 

 

 

 

 

 

• Additional Issues:
• Patients must receive premedication prior to receiving paclitaxel to decrease the incidence of hypersensitivity reactions
• (a) Dexamethasone 20mg PO or IV prior to treatment
• (b) Diphenhydramine 50mg and an H-2 blocker (ranitidine 50mg or cimetidine 300mg) IV 30 minutes prior to treatment
• Patients receive both pre and post medication to prevent the fluid retention associated with use of docetaxel.
• (a) Dexamethasone 8mg PO BID starting 1 day prior to treatment and continuing for 2 additional

 

 

 

 

 

 

 

 

• Cabazitaxel (Jevtana®)
• Semi-synthetic taxane with poor affinity for P-gycoprotein
• (a) Demonstrated activity in docetaxel resistant cell lines
• (b) Approved for the treatment of hormone refractory prostate cancer previously treated with
• (c) Adverse effects similar to other taxanes
• (i) Requires premedications diphenhydramine 25 mg dexamethasone 8 mg and ranitidine SO

 

C. Epothilones

 

• 1 .Mechanism of Action: Similar to the taxanes work in the M phase of the cell cycle.
• Natural epothilones are macrolide derivatives and have stability and pharmacokinetic problems.

Synthetic agents have been synthesized. The first approved agent being ixabepilone (lxempra).

 

• PD:Binding to microtubules is distinct from taxanes with activity demonstrated in paclitaxel-resistant cell lines.
• PK:Epothilones appear to be poor substrates for Pgp and are not affected by its
• Indication: Metastatic breast Studies ongoing in multiple other tumor types.

 

 

 

 

 

 

 

 

• Toxicities: Dose limiting leukopenia and peripheral
• Additional toxicities: anemia, thrombocytopenia, diarrhea, fatigue, myalgia, and
• Additional Issues:
• Patients must receive premedication with diphenhydramine 50mg and an H-2 blocker (ranitidine 50mg or cimetidine 300mg) IV 30 minutes prior to treatment( no steroid needed).

 

 

 

 

 

 

 

 

 

• D. Miscellaneous Tubulin Agents
• Eribulin (Halaven®)20
• Synthetic analog of the marine macrolide halichondrin B
• MOA: inhibits tubulin polymerization!] Inhibits growth of
• Adverse effects: similar Administration:. Requires dose adjustments based on hepatic and renal function r to vinblastine (neutropenia) decreased incidence of neuropathy compared to vincristine
• Indication: metastatic breast cancer after two agents (including taxane and anthracycline)
•  

 

 

 

 

 

 

rr

 

4. ANTIMETABOLITES

 

 

• 1-Folate antagonists
• Methotrexate (Folex®)
• Pemetrexed (Alimta®)

 

 

 

 

 

 

 

 

• II-Purine analogues 3

 

• Cladribine (2-cda, Leustatin®)
• Fludarabine (Fludara®)
• Mercaptopurine (6-MP, Purinethol®)
• Pentostatin (Nipent®)
• Thioguanine (6-TG)

 

 

 

 

 

 

 

 

 

 

 

 

• Ill-Pyrimidine analogues
• Cytarabine (ara-C, Cytosar-U®)
• Gemcitabine (Gemzar®)
• Fluorouracil (5-FU, Adrucil®)
• Capecitabine (Xeloda®)
• Azacytidine and Decitabine (Dacogen®)

 

 

 

 

 

 

 

36

 

Antimetabolites

 

 

 

 

1. V. ANTIMETABOLITES:

MOA of some anticancer drugs

IPurine & Pyrimidine synthesis          I

I             ,               ,

T                                      Methotrexate

 

,_RI_ib_o_n_u_cl_e_ot_id_e_s

—+

   ,I       Inhibition of

,/’         purine ring &

 

.-–I—–.I

dTMP

 

Deoxy ribonucleotides .                 biosynthesis

t

Alkylating agents Alter structure & function of DNA by cross linking and/or fragmenting DNA

/$–

: ID NA I

 

 

 

Dactinomycin , Intercalate with DNA disrupt DNA function

IProteins

 

 

 

 

 

 

 

 

• The antimetabolites :
• drugs that are structurally related to naturally occurring compounds found in the body (amino acids, DNA, RNA).
• These agents exert their damage on DNA in one of two mechanisms inhibition of cell growth and

 

• I- Compete for binding sites on enzymes
• II- Incorporate directly into DNA or RNA

 

 

 

 

 

 

 

 

 

• Folate antagonists (Methotrexate, pemetrexed)
• Mechanism of Action: Methotrexate inhibits the conversion of folic acid to tetrahydrofolate by competitively inhibiting the enzyme dihydrofolate This results in inhibition of DNA synthesis via blockage of thymidylate and purine synthesis.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

DNA

• •·

 

 

 

 

 

 

 

 

 

• Dosage and Administration:
• Methotrexate is given over a wide range of doses IV, IT, or PO
• High dose therapy (S00-1000mg/m2) require leucovorin rescue until MTX levels are less than 0.1 microM .

 

 

 

 

 

 

 

 

 

 

 

 

“

 

 

 

 

 

 

 

 

 

 

 

 

 

–

— 1,000

:::.

C         100

• ⁰.:,

C

t:        10

u

C

–

8     1.0

X

!-

0.1

e

 

s”!<:’:          0.0 I

0         20       40        60        80       100      120     140

 

 

 

 

 

 

H

 

 

 

 

 

 

 

 

• (a) Leucovorin Rescue
• (i) High dose MTX is lethal unless reversed by leucovorin rescue initiated within 42
• ) ii) Calcium leucovorin is a reduced folate replenish the supply of folate metabolites depleted by MTXl1l enters cells by passive diffusion, requiring serum concentrations to  be much higher  than MTX for rescue effect. It allows DNA synthesis to begin again even in the presence of MTX This process of recovery of DNA synthesis is called “rescue”
• (iii) Leucovorin is available po, IM, and Oral bioavailability varied, good at doses less than 35 mg, above that, ranges from 5-50%.

Half-life is about 3 hours, widely distributed, metabolized in tissues.

 

 

 

 

 

 

 

 

• (iv) Dose is generally started at 15 mg/m2 and titrated according to the MTX serum
• Ill Generally started 12 hours after a 3-6 hour infusion of In regimens where MTX is administered as a continuous infusion, leucovorin is started at the end of the infusion.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

“

 

 

 

 

 

 

 

 

 

 

 

• The rescue (i.e. leucovorin + hydration/alkalinization) can be stopped when the concentration of MTX is less than (0.1 uM), although some algorithms recommend concentrations of less than (0.05 uM).
• Pemetrexed requires premedications with folic acid and vitamin 812 to decrease the myelosuppression.

 

 

 

 

 

 

 

 

• Toxicities:
• Dose limiting leukopenia and thrombocytopenia
• Renal tubular necrosis seen with high dose therapy. Vigorous hydration and alkylation of the urine necessary to decrease risk of kidney damage.
• Additional toxicities: Pulmonary pneumonitis, alopecia, and stomatitis and mucositis

 

 

 

 

 

 

 

 

• Additional Issues:
• Drugs that are highly protein bound may displace MTX from albumin and increase toxicity (sulfonamides, salicylates, phenytoin, and tetracycline)
• NSAIDS compete for renal excretion of MTX and increase levels.
• Vitamin C will acidify the urine and may increase MTX levels
• iv. Precautions: Third space fluids such as ascites, edema, or pleural effusions can significantly influence the volume of distribution and terminal t1/2these patients will usually require prolonged leucovorin rescue

 

 

 

 

 

 

 

 

 

• Purine analogues
• 1 .Thioguanine (6-TG), Mercaptopurine (6-MP)
• Mechanism Of Action: Structural analogues of guanine conversion by the enzyme hypoxanthine guanine- phosphoribosyltransferase (HGPRTase)111incorporated in to DNA and prevent purine
• Indication: In general, purine analogues are only useful for the treatment of leukemia’s (ALL,AML, CLL, hairy cell leukemia)
• Toxicities: Dose limiting leukopenia and Additional toxicities: Liver toxicity and jaundice (much higher with 6-MP), stomatitis, mucositis, rash, nausea, and vomiting

 

 

 

 

 

 

 

 

 

• iv. Other Issues:
• Mercaptopurine metabolized to inactive metabolite by xanthine oxidase Significant dose reductions (75%) required if given concomitantly with allopurinol(a xanthine oxidase inhibitor).

 

 

 

 

 

 

 

 

 

• 2 .Other purine analogues
• Cladribine (2CdA) – an adenosine deaminase-resistant purine analog intracellular phosphyorylation by deoxycytidine kinase to 2CdATP incorporated into DNA producing DNA strand breaks and inhibiting ribonucleotide reductase.
• Fludarabine After rapid dephosphorylation to the nucleoside 2-fluoro-araA rephosphorylated intracellularly by deoxycytidine kinase to the active triphosphate derivative.
• This antimetabolite inhibits DNA polymerase, causes DNA chain termination, and inhibits ribonucleotide reductase and is incorporated into DNA and RNA.

 

 

 

 

 

 

 

 

• Pentostatin (2-deoxycoformycin)- potent inhibitor of the enzyme adenosine deaminaselll accumulation of intracellular adenosine and deoxyadenosine nucleotides!] block DNA synthesis by inhibiting ribonucleotide reductase
• Toxicities: Unique myelosuppression [lmmunosuppressant effect of t-helper cells] that often require prophylactic antibiotics

 

 

 

 

 

 

 

 

 

• C. Pyrimidine analogues
• 1 .Cytarabine (ara-C), Gemcitabine (Gemzar)
• Mechanism Of Action: Structural analogues of the pyrimidine nucleosides cytidine and deoxcytidine.
• The drugs must first undergo conversion to the triphosphate nucleotide, aracytosinetriphosphate (ara-CTP) and difluorodeoxycytidine triphosphate, respectively.
• The triphosphate forms then act as competitive inhibitors of DNA polymerase halting chain

 

 

 

 

 

 

 

 

• Indication:
• Ara-C is most commonly used in combination with other agents for the induction and consolidation of Also used in the treatment of ALL, CML, and meningeal leukemia.
• Gemcitabine has shown activity in the treatment of pancreatic, lung, breast, and ovarian cancer.

 

 

 

 

 

 

 

 

• Toxicities:
• (a) Dose limiting leukopenia and thrombocytopenia
• (b) Additional toxicities: Nausea and vomiting, mucositis , diarrhea, flu-like syndrome,rash
• (c) With high dose ara-C therapy (>1,000 mg/m2) excessive bone marrow depression, central nervous system toxicity, and conjunctivitis

 

 

 

 

 

 

 

 

 

• Additional Issues:
• (a) Often given with allopurinol to prevent tumor lysis syndrome; high dose therapy given with dexamethasone eye drops 1% every 4-6 hours for 7 days following high dose therapy given to prevent conjunctivitis

 

 

 

 

 

 

 

 

 

• 2 .Fluorouracil (5-FU)
• Mechanism of Action: SFU acts as a “false” pyrimidine inhibiting the formation of the DNA base thymidine.
•  

 

 

 

 

 

 

 

 

 

• Indication: 5-FU is commonly used in the treatment of breast, head and neck, and gastrointestinal carcinomas (stomach, liver, colon, and rectum)
• Dosage and Administration
• (a) Variety of dosing techniques that consistently demonstrate increased response rates with continuous infusions compared to IV bolus dosing with varied effects on survival

 

 

 

 

 

 

 

 

• Toxicities:
• (a) Dose limiting leukopenia and thrombocytopenia, and anemia (with bolus administration).
• (b) Dose limiting hand-foot and diarrhea (with continuous infusions)
• (c) Additional toxicities include: Skin discoloration, nail changes, photosensitivity, and neurologic

 

 

 

 

 

 

 

 

• 3 .Capecitabine (Xeloda)®
• Mechanism of action: Orally active prodrug of fluorouracil (5-FU) that is designed to be selectively activated by tumor cells Capecitabine undergoes a 3-step conversion to 5-FU, the last step being phosphorylation by thymidine phosphorylase (TP).
• TP levels are reported to be higher in tumor cells then normal tissues, therefore the systemic exposure of active drug is minimized.

 

• Toxicities: Dose-Limiting: Hand-foot syndrome, Additional toxicity: Nausea, vomiting,fatigue, rash

 

 

 

 

 

 

 

 

• 4. Azacytidine (Vidaza®) and Decitabine (Dacogen®)
• Mechanism of Action: Directly incorporate into DNA and inhibit DNA methyltransferase that causes hypomethylation of DNA Cellular differentiation and apoptosis are believed to result from this effect.
• The cytotoxicity of these agents may also be attributed to the formation of covalent adducts between DNA methyltransferase and active drug being incorporated into DNA,particularly in cells actively dividing.

 

 

 

 

 

 

 

 

 

 

 

 

,.

 

 

 

 

 

 

 

 

• Indication: MOS
• Toxicities:
• (a) Myelosuppressionis the DLT
• (b) Mild gastrointestinal toxicity and infectious complications are also reported with these

 

 

Int   oduction to Board of Oncology.

HORMONAL THERAPY&TARGETED THERAPY

LEC 5

 

 

 

 

1. ANT/ESTROGENS

 

 

 

 

• Mechanism of Action: inhibit nuclear binding of the estrogen receptor, blocking estrogen stimulation of breast cancer This tamoxifen receptor complex translocates to the nucleus inhibiting DNA synthesis.
• .B: tamoxifen blocks estrogen receptors in other hormone sensitive cancers.
• Indication: Treatment of estrogen-receptor positive breast cancer

 

• Toxicities:
• These agents can induce menopausal symptoms Hot flashes, nausea, and vomiti
• Additional toxicities : vaginal bleeding, bone pain, menstrual irregularities, headache, and depressio
• Rare toxicities include retinal toxicity and thromboembolic disorders.
• Concomitant coumadin therapy m1ay increase your risk of bleedi
• The risk of cancer and tamoxifen therapy is still controversial with the risk of endometrial approximately 3x the normal   The risk of liver cancer in humans has not been firmly established

 

 

 

 

B.AROMATASE INHIBITORS

 

• 1 Aminoglutethamide (Cytadren)
• Mechanism of Action: cause a “medical adrenalectomy”.. Aminoglutethamide prevents the conversion of cholesterol to
• Since aminoglutethamide is a nonspecific aromatase inhibitor,. it also inhibits the production of glucocorticoids, mineralcorticoids, and androgens in addition to
• Indication: treatment of metastatic breast and prostate

 

• Toxicities:
• Neurologic- lethargy, nystagmus, dizziness
• Dermatologic- allergic rash (usually will respond to dose reductions) accompanied with fever and malaise
• Endocrine- adrenal insufficiency (facial swelling, hyponatremia) and mineralcorticoid deficiency are common if replacement  therapy not given. Hydrocortisone 20mg BID and Fludrocortisone 0.1mg every other day are commonly used.
• Miscellaneous 1Nausea, vomiting, l,eukopenia, thrombocytopenia

 

 

• 2 Anastrozole, Letrozole, & Exemestane
• 1Mechanism Of Action: Selective non-steroidal aromatase inhibitors that lower estradiol levels without changing corticosteroid synthesis

 

• Indication:
• Anastrozole has recently been indicated for adjuvant treatment of postmenopausal women with hormone receptor positive early breast
• Anastrozole, and letrozole first-line for locally advanced or metastatic breast
• Anastrozole,. letrozole, and exemestaneindicated foradvanced breast cancer in patients who have progressed on tamoxifen.
• Toxicities: GI disturbances, hot flashes, thromboembolic disorders, weight gain, and edema

 

 

IL LEUTEINIZ NG HORMONE-RELEASING HORMONE ANALOGS (LHRH), (GOSERELIN, LEUPROLIDE) and

ANTAGON STS (Degarelix)

 

• !Mechanism of Action: binds to FSH-LIH-RH receptors folllowed by down regulation of the receptor through a negative feedback
• Degarelix unique long-acting, synthetic peptide with gonadotrophin-releasing hormone (GnRH) antagonistic properties.
• Degarelix targets and blocks GnRH receptors located on the surfaces of gonadotroph cells in the anterior pituitar
• No tumor flare should be seen with
• Indication: Advanced prostate and breast cancer

 

 

 

 

 

 

 

 

 

 

 

• Toxicities:
• 1 .Hot flashes, impotence, reduced libido, Gd disturbances (nausea, vomiting, constipation), local pain at injection site, gynecomastia, and peripheral edema
• 2 . Because of the initial surge in UH, FSH, and ultimately testosterone an initial disease flare (manifested as bone pain) may be seen if patients not treated with antiandrogens prior to treatment

 

 

 

Ill. ANTIANDROGENS (F UTAM DE, BICALUTAM DE, AND NILUTAMIDE)

 

• Mechanism Of Action: Nonsteroidal antiandrogens which competitively inhibit the enz 5-allpha reductase inhibit                                                                                the binding of androgens (testosterone) to the peripheral receptor
• Indication: Used in combination with LHRH analogs
• Dosage and Administration
• 1 .Flutamide 250mg TID PO
• 2 .Bicalutamide 50mg QD PO
• 3 .Nilutamide 300mg QD x l month, then 150mg QD PO
• Toxicities: Gynecornastia hot flashes, increase in liver enzymes (SGO LDH), nausea, vomiting, diarrhea, and visual disturbances

 

MISCELLANOUS HORMONAL AGENTS

 

 

 

 

• Estramustine (Emcyt¥,,)
• Mechanism of Action: Originally developed as an all<ylating agent estramustine is an estradiol molecule linked to a nitrogen mustard through a carbamate ester
• Indication: Advanced prostate
• Dosage and Administration: Administer 1 hour before or 2 hours after meals
• Toxicities: GI disturbances (nausea, vomiting), edema, cardiovascular toxicity, thromboembolic events, and gynecomastia

 

TARGETED THERAPY

 

 

 

 

 

Antibody structure:

 

 

light chain

 

disulphide bonds heavy chain

variable region

 

 

 

 

 

constant region

 

 

 

 

Cancer is a multistep process

Cures need to attack many features of tumors

 

 

 

 

 

 

 

1. Monoclonal antibodies:

 

Antibody Structure

 

 

 

Murine

 

H.umanized

Chime:ric

 

 

 

 

 

Toxin (e.g., radiation}

lmmunoconjugate                                            Human

 

 

 

 

 

 

Understand Names!

 

• -omab 1Muri
• -Ximab
• -Zumab human
• -Umab human

 

 

 

 

What’s following binding:

 

• 1–ADCC: Antibody dependent cell cytotoxicity

 

CD 60, Fe ·RIil       arse    n igen (I.e. CD20 or HER2/ne I	C o me,
	3.    K a o age

 

3. Targ,etingSignaIi ng cascade:

 

Ligand Ligand-binding

domain

 

 

 

 

01Pl3K

1

–.1 Ras I[ ]

‘Y

 

 

PTEN     –II Akt I

+

 

I           

Ra.f..

  MEK   

STAT 3:/5 I

1    MAPK  1:

‘Y

110

II

 

 

 

Survival                                    Proliferation

 

 

 

 

 

4. Targeting on,cogene:

Figure  1:   Potenl!lal  Mechanisms  of  Action  of  T….stuzumab.   A)   Deg,….dation.   Binding   of   tnlslruzum;;,b  can   trigger the  ‘ntemali:zallorn  and  degradation  of  HEFt2.  B)  Block ng  Intracellular  signaling.  Binding of  trastuzumat,   can red•uce or inflitiit si9na.11ng patnways. suctl as the Pl3-l<inase pathway. C.)1mmuno1ogica•1. Tt.asruzumab can ·1:1e ro,;ognll!:ed by ce!ls of the irnrnvne ,a;y,a;tem and h IP guide their .ittt<<;:I<;; on lh8 breast earu:;e,r cellcS.

 

 

 

 

 

 

5.  lnduction of apoptosis

 

• Directly : (targeting antiapoptptic proti,ens)

 

• Indirect: lbritumomab  increase IC Ca+2 leve

 

 

Problems of therapy

 

1.lnfusion reaction: as a result of possible reaction of immune systemrelease ofinflammatory mediators.

• Result in hypotension,fever,rigors,rash&anaphylaxis.
• Premedication -slow infusion
• Activation of latent infection: Hepatitis B reactivation.
• progressive mulifocal leucoencephalopathy {PML) due to immune impairement.
• Gl,renal &CV complications

 

 

Signal transduction arrest:

• Signal transduction :occurs when an extracellular

signaling molecule activates a cell surface receptor. In turn, this receptor alters intrace·llular molecules creating a response.

There are two stages in this process:

• A signaling mollecule activates a specific receptor protein on the cell membr
• A second messenger transmits the signal into the cell, eliciting a physiological r

 

Protein Kinase

• Is kinase enzyme that modifies other proteins by ch mically adding phosphate groups to them (phosphorylation)

 

• The phosphate is often taken from ATP

 

• Phosphorylation of proteins by kinases is an important mechanism in communicating signals within a cell (signal transduction)

and regulating cellular activity, such as cell division.

 

TYROStNE KINASE STRUCTURE

 

Transmembrane Domain

 

 

.,._                                  Intracellular

Domain

 

 

 

 

 

 

 

 

 

 

RT        c ure/function

30

 

 

 

 

 

 

Tyrosine Kinase

 

• Is an enzyme that can transfer a phosphate group from ATP to a protein in a cell.

 

• It functions as an “on” or 110:fr’ switch in many cellular functions.

 

• The phosphate group is attached to the amino acid tyrosine on the pro.

 

 

Tyrosine Kinase Types

 

1. Receptor tyrosine kinases

eg: EGFR, PDGFR, FGFR

 

2. Non-receptor tyrosine kinases

eg: SRC, ABL, FAK and Janus kinase

 

.a-helix in the

membrane

Signal-molecule binding site

 

Plasma

 

 

 

Tyrosine-kinase receptor proteins (inactive monomers)

 

33                  (a) Inactive tyrosine-kinase receptor system

 

 

 

 

Signal molecules

Activated

 

 

 

 

 

 

 

 

.   -$7fA\►DP

Activated tyrosine-kinase receptor (phosphorylated dimer)

• Cellular

►                      —

response

 

— ► Cellular

response

 

 

34                                  (b) Activated system

 

 

 

 

 

 

Targeted Therapy

 

• is a type of medication that blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor

 

• rather than by simply interfering with all rapidly dividing cells (e.g. with traditional chemotherapy).

Tyrosine Kinase Inhibitor

 

1. BCR-ABL Tyrosine Kinase Inhibitors eg: Imatinib, Dasatinib,

 

2. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

eg: Gefitinib, Lapatinib.

 

3. Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors eg: Semaxinib, Vandalinib, Sunitinib, Sor