Blood And Lymph- Anticancer Drugs By Boy Bridges

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Blood and Lymph- Anticancer Drugs by Boy Bridges

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Blood and Lymph- Anticancer Drugs by Boy Bridges

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Induction, Intensification, Maintenance definitions

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Induction (remission)
-Initial intensive treatment
-Usually achieves a remission with no evidence of leukemic cells in blood or marrow

Consolidation or Intensification
-To eradicate clinically undetectable disease
-A 2nd, 3rd or 4th intensive course of chemo. Usually given to increase chances of a cure.

Maintenance (continuation)
-Continued treatment to prevent relapse
-Less intensive chemo given for a long time. Aim is to kill any remaining leukemia cells.

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Anticancer therapy vs. Antimicrobial therapy

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Antimicrobial: low continuous doses
Cancer chemo: high intermittent doses

To ‘cure’ cancer, need 100% cell kill; Can’t rely on host immunological defense to kill remaining cancer cells

Cure- disappearance of any evidence of tumor for several years & high probability of normal life span

Clinically complete remission: tumor size decreased to a size no longer detectable clinically

Anticancer drugs: limited selective toxicity

Continued mitotic activity is one target (mitotoxicity hypothesis)
Selective toxicity to cancer cells is limited by considerable toxicity to normal cells

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Selective Toxicity:
Which cells are most vulnerable to chemotherapy?

What else can make successful chemotherapy difficult?

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Rapidly dividing cells are most vulnerable to chemotherapy
Rapidly dividing, normal tissues too!!
-Bone marrow
-GI tract
-Hair follicles

Some cancers are slow growing (‘slow’ cell division)
-(e.g., colon and lung carcinoma)
-makes successful chemotherapy difficult

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Tumor Determinants for chemo responsiveness...

Host Determinants for chemo responsiveness...

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Tumor Determinants
Growth fraction; tumor mass doubling time
Total tumor burden
Cell cycle phase
Drug resistance

Host Determinants
General health status
Immunocompetence
Tumor Site

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Growth Fraction, Tumor Mass doubling time

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Growth Fraction
% of tumor that is growing
Solid tumors – growth depends on nutrient availability and vascularization; diffusion limited growth; center may be necrotic
larger growth fraction --> increase drug susceptibility


Tumor mass doubling time
varies with tumor
Burkitt’s lymphoma: 24 hr
breast tumor: 100 days
faster doubling time--> increase drug susceptibility

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Tumor Growth Kinetics: Solid Tumors

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Most tumors do not grow “rapidly” like leukemias and lymphomas

Growth rate decrease as neoplasm size increase
-Outgrows ability to maintain blood supply
-Not all cells proliferate continuously

Compartments
-Dividing cells vs non-dividing cells(varies; may be ~5% tumor volume)
-Only population susceptible to most anticancer drugs – ie dividing cells

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Tumor Cell population is 'continuously changing' as a complication for effective treatment

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Number of dividing vs resting cells changes

Biochemical/biological character changes

Number of cells than can metastasize changes

Tumors differ in same person from day to day

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Log kill hypothesis

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Cure
-Need to eliminate 100% of cancer cells

Each dose kills a certain FRACTION (not number) of cells

The fraction killed is dose-dependent
-Chemotherapy is limited by the drug toxicity (dose-limiting toxicities)

Repeated doses are needed and cell kill follows first order kinetics

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Total Tumor Burden (Size)

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Clinically detectable tumor
-1 x 109 cells (1 cm)

Lethal tumors
-1 x 1012 cells

Larger tumors are harder to kill
-more difficult for drugs to penetrate; poor vascularization
-many cells not proliferating; less sensitive to drug therapy
-more metastasis occurring
-more therapy (time) required, more toxicity

*increase tumor size, decrease drug susceptibility

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Cell-Cycle Specific... which phases are these?

What about cell-cycle non-specific?

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Cell-cycle specific:
S Phase (DNA Synthesis) and M Phase (prophase, metaphase, anaphase, telophase); mitotically active and dividing.
-Cells must be mitotically active for drug to produce its effects
-Drug target is only available at a particular phase of the cell cycle
-Effective for high growth fraction malignancies
-Slow growing tumors with a small growth fraction are less responsive

Cell-cycle nonspecific:
hit it anywhere. chemically react with the DNA. doesnt matter if it's cycling or not.
-Drug effect may be enhanced but not dependent on mitotic activity
-Effective for both low growth fraction malignancies as well as high growth fraction malignancies

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Mechanisms of Tumor Resistance

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Decreased drug uptake
Increased drug efflux

Decreased drug activation
Increased drug inactivation

Overexpression of drug target
Mutation of drug target
Increased repair of drug damage

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Multidrug Resistance

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Decreased drug accumulation
Efflux pumps – drugs pumped out
An issue for natural product drugs*

**P-glycoprotein (Pgp)
-increase gene expression of a surface glycoprotein

**Multidrug resistance proteins (MRP)
-ATP-binding cassette (ABC) transmembrane superfamily (MRP1-MRP9)

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Multidrug Resistance (MDR) genes

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Pgp expression
-certain secretory tissues
-capillary endothelial cells in brain

MRP expression
-virtually all normal epithelial cells
-colon, liver, adrenal, pancreas, kidney

MDR most likely a natural defense mechanism against harmful substances
-Remove toxic metabs and xenobiotics from cells into urine, bile and the intestinal lumen
-Transport out of the brain across BBB

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Toxicity: Therapeutic Index

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Therapeutic effects on the tumor and toxicity are dose related

The therapeutic index (median toxic dose/median effective dose) for most chemotherapeutic agents = 1

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Adverse Effects / Toxicities

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Common
-Nausea and vomiting, stomatitis, mucositis, alopecia and myelosuppression (predisposes to infection)

Unique (confined to specific agents)
-Cardiotoxicity – doxorubicin
-Pulmonary fibrosis – bleomycin

Hyperuricemia (from tumor burden)
adenine + inosine = hypoxanthine (HX)
HX -> X -> uric acid -> kidney damage
xanthine oxidase mediated (allopurinol)

Duration widely variable:
Transient: Nausea & vomiting (NV), alopecia
Reversible: Bone marrow depression
Irreversible: Cardiac, pulmonary & bladder toxicities

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Alkylating agents

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Nitrogen mustards
-Cyclophosphamide,
-mechlorethamine,
-melphalan

Nitrosoureas
-Carmustine
-lomustine

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Platinum complexes

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Cisplatin

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Antimetabolites

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Antifolates
-Methotrexate

Pyrimidine antimetabolites
-5-Fluorouracil & capecitabine
-Cytarabine & gemcitabine

Purine antimetabolites
-6-Mercaptopurine & 6-Thioguanine

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Alkylating Agents

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Form highly reactive alkyl groups
-covalently bind to nucleophilic targets
-DNA, RNA, and proteins
-DNA modification 1o MOA for cell death but protein modification may play a role

Mono- and bifunctional

Primary mechanism of antitumor action
-Alkylation of DNA
-N7 position of guanine is the major site
-Other bases alkylated to lesser degree(N1 & N3 of adenine, N3 of cytosine, and O6 of guanine)

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Alkylation causes

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Alkylation causes
**Excessive cross-linking (bifunctional)
-Cytotox correlates very closely with interstrand cross-linkage of DNA

**DNA strand breaks (monofunctional)
-Depurination by excision of guanine residues, leading to strand breakage by repair enzymes

Miscoding of DNA
-Causes mispairing with thymine

Affect both cycling (CCS) and noncycling cells (CCNS)

Replicating cells are most susceptible
-in late G1 and S phases
-express block in G2

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Alkylating Agents Toxicities

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Affects cells with rapid turnover
NV (most common); alopecia
Bone marrow depression
Mucosal toxicity
-oral mucosal ulceration and intestinal denudation
Potentially carcinogenic, mutagenic, teratogenic
-Leukemogenesis; acute nonlymphocytic leukemia – up to 5%
Reproductive system toxicity
-often cause permanent amenorrhea and irreversible azoospermia

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Alkylating Agents Resistance

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increase activity of DNA repair pathways

decrease drug uptake

increase intracellular concentration of nucleophilic substances (dilutional effect)
-principally thiols that detoxify electrophilic intermediates (ex. glutathione, methallothionein)

increase metabolism to inactive metabolites

exception- nitrosoureas generally lack cross-resistance with other alkylating agents

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Nitrogen mustards

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Cyclophosphamide
Mechlorethamine
Melphalan

Clothes pin structure (bifunctional**)
**Crosslink DNA

In general ...
produce lots of toxicities ...
**Bone marrow depression (BMD)
-dose limiting toxicity
produce ammenorrhea and male sterility
potentially carcinogenic, mutagenic, teratogenic

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Cyclophosphamide... what do you need for activation? Adverse effects?

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Most used & versatile alkylating agent
Broad spectrum
Requires hepatic activation (P450)
-a prodrug requiring activation in liver

Adverse Effects:
**BMD (dose-limiting effect)
Broad spectrum – also used as an immunosuppressant

**Hemorrhagic cystitis (acute dose-limiting effect)
-caused by metabolite acrolein
-aggressive hydration and use *Mesna or *N-acetylcysteine (NAC) to limit toxicity

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Hemorrhagic cystitis**

how do we prevent it?

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Hemorrhagic cystitis is diffuse inflammation of the bladder leading to hemorrhage. This is seen most often in cancer patients as a complication of cyclophosphamide therapy. Refractory bladder hemorrhage may require cystectomy for control of bleeding

Hemorrhagic cystitis from cyclophosphamide can be prevented through aggressive HYDRATION and the use of mesna or N-acetylcysteine, which neutralizes the toxicity of acrolein, a metabolite of cyclophosphamide.

Mesna = 2-mercaptoethane sodium sulfonate

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Alkylating Agents:
Nitrosoureas

what's it good for treatment of?

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Carmustine (BCNU)
Lomustine (CCNU)

Bifunctional alkylators
-May alkylate or crosslink

Do not require enzymatic activation
-Spontaneously breaks down (hydrolyzes) to an alkylating intermediate

Highly lipophilic --> crosses BBB*
-Useful for treating BRAIN TUMORS!

*react with everything... so it's toxic

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Nitrosoureas Toxicities

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Profound and Delayed BONE MARROW DEPRESSION (thrombocytopenia and leukopenia)
FYI: must monitor for at least 6 weeks after a dose

CNS, renal, hepatic & pulmonary toxicity are also dose limiting

Bone marrow and pulmonary toxicities are a function of lifetime cumulative dose

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Alkylating Agents -Platinum Complexes:

Cisplatin...use.

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Use
One of the most commonly used drugs
Broad range of antitumor activity;
-**Testicular, ovarian and bladder cancer
-Platinum analogs: foundation of treatment of head and neck, esophagus, lung and colon cancers

Carboplatin – 2nd generation analog
-Less TOXIC in all AE except BMD (dose limiting)
-Significantly less renal and GI tox than cisplatin

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Cisplatin properties?

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Properties
Inorganic metal complex
Water replaces chloride
-Creates reactive molecule
-Low chloride concentrations favor process
-inside cells
-urine
Causes inter- and intra-strand DNA crosslinks*
CCNS (kills in all cell cycle stages)

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Cisplatin is the worst in which side effects/toxicities?

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Acute
One of the most emetogenic chemo drugs
-**Severe NV in almost all patients
FYI: managed with prophylactic antiemetics
aprepitant + ondansetron + dexamethasone

*Anaphylactic-like reactions
-FYI: Epinephrine, corticosteriods, and antihistamines effectively alleviate symptoms

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Delayed toxicities

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**Nephrotoxicity:
-One of the most nephrotoxic drugs
-Cumulative, dose-related **renal tubular damage (dose limiting -toxicity)
-Abrogated by hydration (pretreatment) and chloride diuresis
-**Amifostine – cytoprotective agent
metabolized to release a thiol metabolite – (acts as a scavenger)

**Neurotoxicity (commonly associated with use)
-peripheral motor & sensory neuropathy
-Ototoxicity (hearing loss)

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Antimetabolites. name some.

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Antifolates:
-Methotrexate

Pyrimidine Antimetabolites:
-5-Fluorouracil & capecitabine
-Cytarabine
-Gemcitabine

Purine Antimetabolites:
-6-Mercaptopurine
-6-Thioguanine

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Ribonucleotide reductase.. what does it do?

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converts ribonucleotides into deoxyribonucleotides (AMP --> dAMPetc)

energy conserving process

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Antimetabolites - Antifolates: Methotrexate uses?

What is it an analog of?

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USES
-**Treatment of leukemias; lymphomastrophoblastic neoplasms; breast, head and neck, and lung carcinomas; osteosarcoma; soft-tissue sarcomas; carcinoma of GI tract, esophagus, testes
-GVHD (prophylaxis)
-**Psoriasis
-**Rheumatoid arthritis

Folic acid analog (antagonist)
-inhibits dihydrofolate reductase (DHFR)
-leads to partial depletion of tetrahdyrofolate cofactors
-interrupts de novo synthesis of TMP and purine nucleotides

Requires transporter to enter cells

Kills cells during S phase (CCS)

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What is Leucovorin Rescue?

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Leucovorin rescue:
Leucovorin
-fully reduced folate coenzyme
-replenishes intracellular pool of tetrahydrofolate cofactors
-**reduces toxicity (DHFR inhibition) in normal cells (BM, GI)

How? Debated. May be transport or polyglutamate differences

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Methotrexate Side effects/toxicity

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**BMD (dose-limiting)
**GI ulceration,
**mucositis
Renal toxicity (high dose)
Hepatotoxic with chronic use (fibrosis, cirrhosis)

remember the first three

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Antimetabolites
pyrimidine analogs:

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5-Fluorouracil (5-FU)
-Capecitabine
-orally active prodrug of 5-fluorouracil

Cytarabine (ara-C)

Gemcitabine

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5-Fluorouracil uses?

(know this)

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Uses:
-breast, colon, head and neck, pancreas, rectum, or stomach carcinomas

One of most widely used agents
-Topical treatment of basal cell carcinoma
-Breast cancer
-One of few with effect in colorectal cancer

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You have to convert 5-Fluorouracil
to a ___ by adding a ___ in order to work,

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it's a nucleobase
nucleoside has no phoshate. add a phosphate and it's a nucleotide.

this needs to be converted to a nucleotide to work.

5-Fluorouracil
Converted in target cells to 5F-dUMP
-ie nucleobase -> nucleoside -> nucleotide
5F-dUMP covalently binds to thymidylate synthetase with FH4 (reduced folate)
Blocks conversion of dUMP to TMP
-decrease TTP & inhibition of DNA synthesis
-qthymineless death
Also converted to FdUTP and FUTP
-Can incorporate into DNA and RNA
-Inhibits DNA & RNA synthesis

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5-Fluorouracil: Resistance

(not focused on!)

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Increased thymidylate synthetase (TS) or its natural substrate dUMP
Deletion of activation enzymes
-ie conversion of base to ribo- or deoxynucleos(t)ide
Decreased affinity of TS for dUMP

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5-Fluorouracil
Side effects/toxicities

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**GI mucositis – dose limiting with infusion

**BMD – dose limiting with IV bolus

*Leucovorin enhances cytotoxic effects as well as toxicities

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Antimetabolites
Pyrimidine analogs:
Cytarabine is a prodrug converted into what to do what? what is it used for?

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(aka cytosine arabinoside or ara-C )
Prodrug converted to ara-CTP
-competes with dCTP & inhibits DNA synthesis

CCS for S phase

FYI: Rapidly cleared
-86% - 96% of dose deaminated
-requires constant infusion over 5-7 days

Uses: Hematological (AML, ALL, non-Hodgkin’s lymphoma)

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Cytarabine
Side effects/toxicities

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BMD (dose limiting)
Stomatitis
Hepatotoxicity
Hyperuricemia (potential crystalluria)
-related to treatment of hematological malignancies

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Antimetabolites
Pyrimidine analogs:
Gemcitabine

tell me everything

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Gemcitabine
Use – breast, nonsmall cell lung, pancreatic, ovarian cancer
Deoxycytidine analog
-phosphorylated to mono-, di-, and triphosphate
Mechanism of action
-**inhibits ribonucleotide reductase; decrease dNTPs
-inhibits DNA polymerase
-incorporates into DNA (chain termination)

Toxicity – **Myelosuppression (neutropenia) (dose limiting)

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Antimetabolites
Purine analogs:

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6-Mercaptopurine (6-MP)
-hypoxanthine analog

6-Thioguanine (6-TG)
-guanine analog

For our purposes, these two are more alike than different

*there are bases. they have to be converted to the monophosphate to work. and because they are purines, we're going to muck up the A's and the G's

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6-Mercaptopurine & 6-thioguanine uses

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Acute lymphocytic leukemia (ALL)
Acute myelogenous leukemia (AML)
Chronic myelogenous leukemia( CML)

aka **ALL , AML , CML

it's a base that needs to become a nucleotide.

MoA:
**inhibit synthesis of purine nucleotides
-leads to decreased RNA & DNA synthesis
(you have less GTP, ATP, dATP, dGTP)

Can incorporate into RNA & DNA
-leads to non-functional RNA & DNA

Both are CCS (S phase)

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What is 6-Mercaptopurine metabolized by?

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metabolized (inactivated) by xanthine oxidase.**

6-TG requires deamination before it can be metabolized by XO

The dose of 6-MP must be lowered when **allopurinol used concurrently (xanthine oxidase inhibitor)

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Why use allopurinol??

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To protect the kidneys against uric acid damage

Uric acid: product of nucleic acid breakdown

Excessive uric acid production in pts w/ leukemia, lymphoma, and other malignancy
-especially when treated with antineoplastic drugs

High levels of uric acid presented to kidneys can cause precipitation and crystal damage or renal stones

Allopurinol inhibits uric acid production by inhibiting xanthine oxidase.

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6-Mercaptopurine & 6-thioguanine
resistance and side effects/toxicities

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Resistance:
decreased HGPRT
increased alkaline phosphatase
-removes phosphates from nucleotides

Side effects/toxicities:
BMD (dose limiting)
Hyperuricemia (potential for crystaluria)
Hepatotoxicity
-~ 1/3 pts show some cholestatic jaundice

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Natural Products
Antimitotic Drugs
Vincristine
Vinblastine
how do they work?

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Derived from periwinkle plant
Binds to beta-tubulin
-**inhibits microtubule polymerization
-arrests mitosis
CCS for M phase

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MicrotubulesDynamic Instability Model, describe the growing end and the shrinking end

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Growing end
-STABLE tip w/ GTP-cap, adds new dimers
-If high [tubulin], dimers added quickly, otherwise it slows down

Shrinking end
-has GDP and tip is UNSTABLE – disassembles
-At some [tubulin], GTP hydrolysis on beta subunit exceeds addition of new dimers

*A few molecules of vincristine or vinblastine bound to plus end suppresses microtubule dynamics

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Natural Products
Vinca alkaloids

Vincristine uses, side effects,

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Uses
**Leukemias, lymphomas (non-Hodgkin’s )
**Treatment of choice to induce remissions in lymphocytic leukemia

Side effects/toxicities:
**Neurological toxicity (dose-limiting)
Peripheral sensory neuropathy
Autonomic – orthostatic hypotension, sphincter problems, paralytic ileus (severe constipation)
Cranial motor nerves – isolated paresis and/or paralysis of muscles (extraocular and vocal cord)
**WARNING: FATAL IF GIVEN INTRATHECALLY
produces devastating and invariably fatal central neurotoxicity

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Vinblastine

uses and side effects

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Uses
Hodgkin's and non-Hodgkin's lymphoma; testicular cancer; breast cancer; Kaposi sarcoma

Side effects:
**Myelosuppression
dose limiting BMD (vinBlastine )
Neurological minimal at low doses

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Antimitotic Drugs
Taxanes:
Paclitaxel
Docetaxel

how does it work?

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Natural product from yew tree bark
-Now produced by plant cell fermentation (PCF) technology

**Binds to tubulin and hyperstabilizes polymerized microtubules so that mitotic spindle can’t breakdown;activates apoptosis

CCS – arrest mitosis

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Paclitaxel

side effects, uses

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**Peripheral neuropathy (dose limiting)
**Bone marrow depression (dose limiting)
-manifests as neutropenia

Uses
Treatment of breast, nonsmall cell lung, and ovarian cancers

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Docetaxel

side effects, uses

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**Neurotoxicity (dose limiting)
-neurosensory and neuropathy
**Bone marrow depression (dose limiting)
-manifests as neutropenia
**Fluid retention

Uses
breast cancer; nonsmall cell lung cancer; prostate cancer; gastric adenocarcinoma; squamous cell head & neck cancer

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Natural Products - Epipodophyllotoxins:
Etoposide

How does it work? resistance? uses?

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Etoposide
**Inhibits topoisomerase II
-Causes DNA damage through strand breaks and leads to apoptosis
CCS - blocks at S-G2 interface

Resistance
-P-glycoprotein
-mutation or decrease Topo II expression
-mutation of p53
**BMD is dose-limiting

Uses:
refractory *testicular tumors; *small cell lung cancer
-lot’s of off label use – leukemias, lymphomas

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Natural Products –
Camptothecin Analogs:

Irinotecan
Topotecan

uses for each, how they work?

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Topotecan
*Ovarian and *small cell lung cancer

Irinotecan
Metastatic *colon carcinoma

**Topoisomerase I inhibitors
stabilizes cleavable complex
religation of cleaved DNA cannot occur
cleavable complexes accumulate
-ie ss-DNA breaks (repairable, not lethal)
replication fork hits it --> ds-DNA break
-cells cannot efficiently repair
S-phase specific

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Toxicity / Side effects of topotecan and Irintecan

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Topotecan
**BMD (dose limiting)
neutropenia
may also cause anemia and thrombocytopenia

Irinotecan:
**Diarrhea (dose limiting)
early and late onset forms
potentially fatal
**BMD (dose limiting)
neutropenia
may cause anemia, leukopenia and thrombocytopenia

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Natural Products - Antibiotics :
Dactinomycin

how does it work?

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Dactinomycin (aka actinomycin D)
Binds to DNA through **intercalation
**Blocks DNA and RNA synthesis
-DNA-dependent RNA polymerases more sensitive than -DNA polymerases

Dactinomycin intercalates between two base pairs and distorts the DNA to inhibit all forms of DNA-dependent RNA synthesis
Intercalates between adjacent GC base pairs

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Dactinomycin side effects

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Side effects
**BMD (dose limiting)
-pancytopenia
**Stomatitis, **proctitis
Increased skin pigmentation if exposed to radiation therapy

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Natural Products - Antibiotics
Doxorubicin
Daunorubicin

how do they work?

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**Intercalates into DNA
-*blocks DNA and RNA synthesis

**Inhibits topoisomerase II
-leads to strand breaks and apoptosis

*Free radical formation
-powerful iron chelator; Fe-doxorubicin complex produces free radical; cleaves DNA and cell membranes

Maximal effects in S phase but not CCS

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Use, resistance, side effects for both?

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Doxorubicin – broad spectrum
Daunorubicin
-*acute lymphocytic (ALL) and nonlymphocytic (ANLL) leukemias

Resistance: MDR (**P-glycoprotein)

Side effects:
**Bone marrow depression (dose limiting)
FYI: Vesicants – One of the most important to look out for extravasation injury (due to widespread use)

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(rubicin ... red ... ruby .. heart!!)

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**Cardiotoxicity (rubicin ... red ... ruby .. heart!!)
Chronic, cumulative dose related, often irreversible
-Effect may be delayed for months or years
-Manifests as congestive heart failure
-unresponsive to digitalis
-50% mortality rate
Risk factors: irradiation, cyclophosphamide

*Mechanism
generation of *free radicals through an iron-dependent, enzyme-mediated reductive process

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Natural Products - Antibiotics
Bleomycin
MoA

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Bleomycin
MOA – unique!!*****
Causes DNA strand breaks
-**Binds to DNA
-Chelates metal ions [primarily iron, Fe(II)] that reacts with O2 to produce superoxide and hydroxide *free radicals
-Catalyzes single-stranded (ss) and double-stranded (ds) cleavage of DNA
-The DNA fragmentation is due to **oxidative damage by a **DNA-bleomycin-Fe(II) complex

CCS drug – causes accumulation of cells in G2

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Bleomycin
side effects

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**Pulmonary toxicity (dose limiting)
**Significant cutaneous toxicity
-hyperpigmentation, skin ulceration, stomatitis, mucocutaneous reactions

**Minimal myelosuppression:
(significant advantage - often used in chemo regimens)

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Bleomycin
Pulmonary Toxicity
what can be potentially life-threatening?

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Starts as nonspecific pneumonitis
-begins w/ dry cough, fine rales, and diffuse basilar infiltrates on x-ray
-radiologic changes may be indistinguishable from interstitial infection or tumor

**Potentially life-threatening pulmonary fibrosis
-may progress to dense fibrosis, cavitation, atelectasis or lobar collapse or consolidation
-fibrosis may be irreversible

Effect is cumulative
-Pulmonary function test not of predictive value

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Bleomycin
Pulmonary Toxicity
Risk Factors

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-Related to total dose
-Age over 70
-Underlying pulmonary disease
-High doses
-High concentrations of oxygen
-Anesthesia or respiratory therapy – may aggravate or precipitate pulmonary toxicity in previously treated patients
-Prior or concurrent radiation therapy

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Natural Products – Enzymes
L-Asparaginase

use
Side Effects

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Use:
Standard agent for treating lymphocytic leukemia including ALL

Side Effects
-**Anaphylaxis and serious allergic reactions
9Coagulopathy
-↑ PT, ↑ PTT, hypofibrinogenemia, CNS hemorrhage
-*CNS (coma, seizures and hallucinations)
-Serious *thrombosis, including sagittal sinus thrombosis
-*Pancreatitis (potentially fatal)
-*Glucose intolerance (can be irreversible)

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Anticancer drugs
Hormones and antagonists:
Glucocorticoids
Prednisone

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Most commonly used glucocorticoid
Suppresses lymphocyte proliferation
May trigger apoptosis

Side effects (remember the steroid man):
Cushing like symptoms
CNS disturbances
Osteoporosis
Metabolic alterations
Myopathy

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anti-estrogens
Tamoxifen

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Non-steroidal anti-estrogen
Mixed agonist/antagonist
Competitively **binds to estrogen receptor
-but affinity much lower than estrogen
Most effective in those that
-Lack endogenous estrogen source
-Postmenopausal or oophorectomy
-Breast tumors that are ER+

Increases bone mineralization; useful in osteoporosis

Adverse effects – **well tolerated
-NV (mild) ~ 25%; Hot flashes ~ 25%
-Infrequently ... hypercalcemia, edema, headache, mild decrease in platelets & leukocytes
-Women using for 7 years have an increases incidence of uterine malignancies

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AROMATASE INHIBITORS
Anastrozole

how do they work?

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Non-steroidal drugs that competitively inhibit

1. **adrenal synthesis of steroids (inhibits conversions of cholesterol to pregnenolone) ~ medical adrenalectomy

2. **Aromatase conversion of androgens to estrogens in peripheral tissues
-peripheral source of estrogen can be important in breast cancer growth in **postmenopausal women

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Bortezomib

use
moa

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Use: *multiple myeloma
*Reversibly inhibits 26S proteasome

*disrupts various cell signaling pathways

Leads to cell cycle arrest, apoptosis, and inhibition of angiogenesis

Side effects
-Bone marrow depression

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Hydroxyurea

moa, use, side fx

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**Inhibits ribonucleotide reductase
-Converts NDPs to dNDPs (eg GDP → dGDP)
-Results in depletion of intracellular dNTP pools leading *to inhibition of DNA synthesis

CCS (S phase specific)

Uses: melanoma, chronic myelocytic leukemia (CML), ovarian cancer

Side effects
**Myelosuppression (dose limiting)
Leukopenia, megaloblastic anemia, thrombocytopenia

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Imatinib

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Imatinib (Gleevec)

**Inhibits Bcr-Abl tyrosine kinase
-competitively inhibits ATP binding site
-decreases tyrosine phosphorylation of proteins involved in BCR-ABL signal transduction (**signal transduction inhibitor)

Use – *chronic myelogenous leukemia
-characterized by Philadelphia chromosome translocation
-translocation results in Bcr-Abl fusion protein, the causative agent in CML

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Anticancer Drugs -
Monoclonal antibodies:
Trastuzumab

how does it work?
what does the HER-2 receptor do?

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Trastuzumab (Herceptin)
Humanized monoclonal Ab to HER-2 receptor
-Binds to and **blocks HER-2 receptor

HER-2 receptor:
-epidermal growth factor family (surface receptor)
-tyrosine kinase that activates downstream signals and enhances metastatic potential and inhibits apoptosis
-HER-2 assoc with aggressive ER- breast cancer & clinical resistance to cytotox and hormone therapy

Increased risk of cardiotoxicity
-asymptomatic decrease in left ventricular ejection volume

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Anticancer Drugs -
Monoclonal antibodies:
Bevacizumab

what kind of agent is it? how does it work?

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Bevacizumab (Avastin)
**Anti-angiogenic agent

*Blocks vascular endothelial growth factor (VEGF) from binding to its receptor
-ie blocks development of new blood vessels
-VEGF is an angiogenic growth factor that regulates vascular proliferation

Approved for metastatic colorectal cancer

GI toxicity (perforation / ulceration)