Anti Cancer

• To cure malignancy
• To improve cure rates (adjuvant therapy)
• To spare organ function (along with radiation)
• To Palliate Symptoms

• There are 2 types, an alkane which is a hydrocarbon chain with only C-C and C-H bonds.
• The other type is an alkyl group which is an Alkane that is missing a hydrogen molecule giving it an unpaired e- so it is very reactive.

• A molecule similar to an essential metabolite that blocks that metabolite's utilization.
• When used in chemotherapy it implies inhibition of the synthesis of DNA, RNA, or protein.

• Anti cancer agents found in nature that inhibit cell replication and need little to no synthetic modification.
• Usually derived from fungi(antibiotics) or plants(plant alkyloids)

• Chlorambucil
• Melphalan
• Cyclophosphamide
• Ifosfamide

• BCNU
• CCNU
• mCCNU
• Streptozocin

• Busulfan
• Thiotepa
• Procarbazine
• Dacarbazine

• Methotrexate
• Pemetrexed
• 5-FU
• ARE-C
• Gemcitabine
• 6-TG
• 6-MP
• Hydroxyurea

• Anthracyclines
• Mitoxantrone
• Actinomycin-D
• Bleomycin

• Vinca Alkaloids
• Podophyllotoxins
• Camptothecins
• Taxanes
• Misc- platinum derived, and I-Asparaginase

• Inhibition of DNA synthesis (like wuinilones inhibiting DNA gyrase)
• Inhibition of mitotic spindle function
• Endermine growth regulation (target ribosomes)
• Acquire resistance
• Anti neoplastics carry much more risk than antibiotics

• Effective chemo doses kill a constant fraction of tumor cells so as the number of cells decreases so does the number killed with each dose.
• complete killing does not occur.

Immunologic mechanisms, or possibly apoptosis of those cells

• When the tumor cells are actively replicating (cell cycling)
• Usually only a small percentage of tumore cells are cycling

• P16
• P21
• P27
• P14arf- indirectly by blocking MDM2 which Blocks P53 which in turn does not stimulate P21 formation allowing progression.

Cells with damaged DNA are allowed to complete the cell cycle.

• As tumors grow rapidly they outstrip their blood supply and may decrease their growth fraction decreasing chemo effectiveness.
• As tumors shrink and the growth fraction increases chemo may become more effective.

• G1 the cell is making the machinery to replicate DNA
• S phase is where the DNA is replicated
• G2 is where the synthesis of mitotic machinery happens
• G0 is the time between mitosis and the beginning og G1

Vinca Alkaloids and Taxanes

Anti metabolites

• Alkylators
• Antibiotics
• Platinum compounds
• These are said to be radiomimetic because they cause DNA damage in non cycling cells

• Action is due to the bonding of alkyl groups to intracellular molecules
• they generate highly reactive positively charged intermediates
• Combine with nucleophilic groups(- charge) like amino, phosphate, sulfhydryl, or hydroxyl groups
• Can have 1 or 2 functional groups
• usually first line- cause vesivles

• secondary malignancies like AML
• Toxicity worse in patients with defective DNA repair genes like ataxia telangiectasia and xeroderma pigmentosa since the drugs cause single or double stranded breaks.

• Decreased transport across cell membranes
• Gene amp of efflux genes
• Increased intracellular thiol concentration- thiols neutralize alkylation
• Increased enzymatic detoc of reactive intermediates
• Alteration in DNA repair enzymes- gene mutation

• Fat soluble so can cross BBB
• Prolonged bone marrow suppression
• Easily degraded
• Used in melanoma and brain tumors commonly
• Streptozocin is used in islet tumors

• an alkylator that is not often used, causes prolonged marrow suppression
• Has some action in melanoma
• busulfan(CML) and procarbazine(hodgkin's and brain tumors) also aren't used any more.

• Part of MOPP protocol for hodgkin's treatment
• Mechlorethamine

• Chlorambucil
• well absorbed orally and active on slowly progressing malignancies like CLL

• Alkylator used in multiple myeloma
• given in high dose bone marrow transplant protocol
• some activity in breast and ovarian cancer.

• Alkylator that is well absorbed orally
• Widely used
• Active intermediates(phosphoramide mustard)
• good for breast cancer, lymphomas and leukemias
• causes myelosuppression

• An alkylator used in testicular cancer, sarcomas, and lung cancer
• Intermediate is acrolein which can cause hemorrhagic cyctitis destroying the bladder
• Can use MESNA to inactivate Acrolein

• Inactivates Acrolein by giving a free thiol group
• Acrolein comes from ifosfamide and cyclophosphamide

An alkylator used in melanoma as well as in the ABVD protocol for Hodgkin's

• Marrow suppression usually after use, recovery in 7-10 days
• Happens more often and for longer with nitrosureas
• Vesicants
• Hemorrhagic cystitis due to acrolein- forced hydration so it does not sit in bladder along with MESNA
• Can cause secondary malignancies due to sub lethal DNA damage.

• Busulfan- Interstitial fibrosis
• Procarbazine- antabuse effect

• Most active during DNA synth
• Inhibit DNA RNA and protein synth

• Anti folates- methotrexate
• Pyrimiding analogues- 5-FU, ARA-C
• Purine Analogues- 6-MP, 5-TG
• Urea Analogues- Hydroxyurea

• Anti folate anti metabolite that blocks dihydrofolate reductase by competing with oxidized folate
• DHFR reduces folate for Thymidylate synthetase which uses it to convert uridine monophosphate to thymidine monophosphate.
• It is not metabolized- half life based on renal clearance
• Weak acid that is soluble at alkaline pH
• does not cross BBB

• Increased production of DHFR by gene amp
• Decreased affinity of DHFR for methotrexate (mutation)
• Decreased uptake by gene amp
• More active if polyglutamated- cancer cells often cant do this.

• Choriocarcinoma
• ALL
• Non Hodgkins Lymphoma
• Cutaneous T Cell lymphoma
• Lun and breast cancer
• Intrathecal- spinal cord chemo
• Causes marrow suppression, rash, mucositis, Hepatotoxicity with chronic use, pulmonary tox

• collects in pleural effusions and ascitic fluid
• then slowly released

• Pemetrexed- used for mesothelioma and lung cancer
• Raltitrexed- used for colorectal and breast cancer

• Used to rescue tumor cells
• as tumor shrinks GF (cells in mitosis) goes down making MTX less effective
• Rescuing the tumor cells brings the GF back up so you can hit with MTX again
• Very dangerous, must be timed right

• Pyrimidines are thymine(uracil in RNA), cytosine
• Purines are guanine and Adening

• Anti pyrimidine (C T U) drug, looks just like uracil but with a flourine at position 5
• Converted to F-Dump which competes with DeoxyUridine MonoPhosphate for Tymidylate synthetase stopping formation of dTMP a precursor to dTTP a dna base
• 5f-UMP gets incorporated into RNA acting as a false pyrimidine.

• Decreased activation of 5-FU (decreased PRPP with allopurinol use)
• Increased activity of TS (gene amp)
• Reduced drug sensitivity of enzyme (mutation)

• Colorectal cancer(non metastatic)- enhanced by addition of reduced folate that makes a complex allowing for another bond between F-Dump and TS completely blocking it
• Breast cancer- used as adjuvant
• GI malignancies

• Mostly GI (mucositis
• Myelosuppression
• Skin- sun sensitivity and venous discoloration

• Cytosince Arabinoside(ARA-C
• Gemcitabine
• Capecitabine- pro drug converted to 5-FU in liver then to active drug in liver and tumor cells- oral admin, mimics 5-FU- tox= hand foot syndrome

• A pyrimidine analogue that is incorporated into DNA, inhibits DNA pol and DNA elongation
• resistance due to- increased activity of cytidine deaminase(inactivates drug)
• decreased activity of deoxycytidine kinase(activates drug
• Decreased affinity of DNA pol for ARA-C- mutation

• AML treatment
• Causes severe BM suppression
• GI mucositis
• Unusual neuro tox- cerebellat dysfunction

• A cytoisine analogue
• similar structurally to ARA-C
• Anti tumor activity against variety of tumors
• Key in treatment of pancreatic cancer- but still not great

• 6-MP and 6-TG
• work by inserting into DNA activated by HGPRT
• this blocks DNA synth
• most important point of attack is the reaction of glutamine and 5-phosphoribosyl-1-pyrophosphate (PRPP) to form ribosyl-5- phosphate, the first committed step in DNA synthesis

• Metabolized to deoxynucleotides and incorporated into DNA
• active during DNA synth
• resistance due to decreased activity of HGPRT- mutation, and increased drug degredation
• used for leukemia
• Cause myelosuppression, mucositis, diarrhea, nausea, and vomiting

• decreases 5-FU activity by inhibiting PRPP which converts 5-FU to Fdump
• increases activity of purine analogues by inhibiting PRPP which is needed for activation

An adenosine analogue with activity in low grade lymphoma.

• unique anti metabolite that is an analogue of urea
• blocks ribonucleotide reductase which is needed to make ribonucleotides into deoxyribonucleotides
• blocks DNA synth
• activ in CML
• causes myelosuppression, nausea, vomiting, and diarrhea

• Anthracyclines- doxorubicin, Danorubicin, Idarubicin, epirubicin
• Anthracenedione- ,mitoxantrone
• Dactinomycin
• Mitomycin
• Bleomycin
• Come form various strains of soil fungis like streptomyces

• Intercalates between DNA and RNA base pairs blockying synthesis
• Inhibits Topoisomerase 2 causing DNA strand breakage
• Generates oxygen and hydroxyl free radicals causing DNA breakage and membrane damage
• resistance mediated by MDR membrane assoc p-glycoprotein(an efflux pump)

• Doxorubicin used in Non hodgkins lymphoma with cyclophosphomide, vincristine, and prednisone
• also in breast cancer, sarcomas, and other tumors
• daunorubicin used in AML
• Idarubicin used in hematolgic malignancy
• Epirubicin used in same manner as doxorubicin

• Cardiac- free radicals have affinity for cardiac muscle
• result is dose dependent cardiomyopathy
• worse with HT or other afterload stress
• aggravated by radiation
• Synergistic with other drugs like herceptin
• can use cardio protective drugs to prevent
• marrow suppression
• alopecia
• severe nausea and vomiting
• secondary malignancy

• An Anthracinedione
• Similar to anthracycline but less active and less toxic
• used in frail patients

• Antibiotic that works by intercalation
• Activity in pediatric tumors like wilms tumor
• causes myelosuppression, severe vesicant

• Antibiotic that works by causing potent cross linking similar to alkylators
• possible preferential activity in hypoxic conditions
• MDR mediated by p glycoprotein
• used in anal cancer with 5-FU and radiation to spare anal function
• can also be used for intra vesical Rx for superficial bladder cancer
• Tox- TTP, often fatal

• Antibiotic used to treat recurrent pleural infections, causes inflammation making the pleura stick tohether.
• Intercalates in DNA
• Produces single and double stranded breaks
• ONLY drug that works predominantly in G2
• resistance is MDR mediated by p- glycoprotein
• Works on Testicular cancer
• Hodgkin's as part of ABVD protocol
• NHL
• Tox: free radical is directly toxic to lung
• Must monitor pulmonary function
• can cause acute anaphylaxis

• Vincristine, Vinblastine, Vindesine, and Vinorelbine
• Derived from periwinkle plant

• Paclitaxel and docetaxel
• Derived from the yew tree

Etoposide and Teniposide

Irinotecan and Topotecan

• Bind to tubulin and cause depolymerization of microtubules preventing spindle formation and thus mitosis.
• MDR mediated by p glycoprotein
• Tox: peripheral neuropathy since MT is similar to neural sheath
• Dose dependent
• Sensory neuropathy is often reversible but motor is not
• Used in Hodgkins, NHL, Lung cancer, Glioma, and Breast cancer(vinorelbine)

• Bind tubulin enhancing MT formation, preventing spindle dissociation stoping mitosis
• MDR
• Paclitaxel used in ovarian cancer
• active in breast and lung cancer
• Tox: Marrow, allergies, myalgia, arthralgia, neurologic, skin (thin fragile nails)

• Emetic, cathartic, antihelminthic.
• Inhibit DNA topoisomerase 2 thus inhibiting DNA and RNA synthesis- cell cycle specific
• MDR
• Works in testicular cancer, small cell lung cancer, NHL, and some others

• Inhibit topoisomerase 1 blocking DNA synth and killing the cell
• Irinotecan used in metastatic colon cancer- causes excessive diarrhea, also has cholinergic effect requiring atropine
• Topotecan- used mostly in small cell lung and ovarian cancer- causes myelosuppression

• Cisplatinum, Carboplatinum, and Oxaliplatinum
• Heavy metals
• Can mould shape
• Act as alkylators
• Neuro toxic
• cisplatinum has nephrotoxicity
• carboplatinum causes myelosuppression
• Oxaliplatinum causes cold intolerance

• platinum complex with 2 Cl- and 2 H3N groups
• curative for most germ cell tumors
• Works well for lung, breast, and unknown primary cancers
• Carboplatinum has the same spectrum but less nephro tox
• Oxaliplatinum has unique activity in colon cancer

• Nephrotoxicity: parenteral and oral hydration
• use mannitol(volume expander) to force diuresis
• Replace K+ and magnesium
• Use Amifostine- a compound that picks up cisplatin metabolites from the tissues
• Neurotoxicity: Ca and magnesium infusions are somewhat protective
• Cold induced neuropathy prevented by avoidance of cold things.

Anti cancer drug from pig serum that inhibit leukemia cells by hydrolysing circulating asparagine- this inhibits tumor growth because most tumors have low asparagine synthetast activity. So protein synthesis is inhibited.

• Anti Estrogenic- Tamoxifen, aromatase inhibitors, progestins, and LHRH analogues
• Anti Androgenic- Receptor block(flutamide/biclutamide) LHRH analogues
• Glucocorticoids

• Blocks the estrogen receptor- given orally
• Tox: Thromboembolic disease
• Endometrial cancer
• Hot flashes
• Retinopathy
• Faslodex is an irreversible blocker of the ER

An aromatase inhibitor that is very toxic and requires sterioud use at same time.

• Anastrozole, Letrozole, and Exemestane
• Tox is caused by estrogen withdraw- osteoporosis, hot flashes, and arthralgia.
• Aromatase inhibitors more activ in post menopausal than tamoxifen.

• Post menopausal because ER is up reg to combat low estrogen levels
• Has an anti estrogen effect on the breast but estrogen effect in the uterus
• Aromatase inhibitors only used in post menopausal when adrenal is making the estrogen

hot flashes, impotence, and andropause

• Pituitary inhibition
• Leuprolide and goserelin- work by decreasing pituitary release of LH and FSH leading to decreased estrogen and testosterone prod
• work for prostate and breast cancers
• Cause flare effect and impotence

• cause malignant lymphocytes to lyse.
• Work in hodgkins and NHL
• Also used in supportive care as anti nauseant, appetite stimulant, reduction of cerebral edema, and analgesic
• Tox: fluid retention, glucose intolerance, proximal myopathy, insomnia, immunosuppression, increased appetite, skin changes, and stress ulcers.

• drugs that block cancer growth/spread by blocking specific molecules that the tumor cells need.
• Tyrosine Kinases, EGF receptors, VEGF receptors, and m-TOR are usual targets

• Receptor and non receptor associated- they block signal transduction
• Iapatinib- used in breast cancer blocks EGFR(her 2 assoc)
• Gefitinib and erlotinib block EGFR(non her2 assoc) both used for non small cell lung ca
• Sunitiniband Sorafanib block VEGF
• Imatinib and Nilotinib work for GIST and CML- Block product of mutated oncogene(non receptor assoc)

• TK inhibitor that blocks cativity of the protein produced by BCR-Abl oncogene in CML
• used for CML and GI stromal tumors( expressing c-kit TK)
• Mutation of BCR-Abl confers resistance
• Tox: Diarrhea, Myalgia, and fluid retention

• Trastuzumab- has cardio tox,
• indicated in Her-2/neu over expressing breast ca
• Cetuximab- used in Sq cell, head and neck Ca, and wild type K-Ras colon cancer
• Panitunumab- also used in Wt K-Ras colon cancer

• Bevacizumab- used mainly in colon cancer
• causes poor wound healing

• CD20- rituxumab- used for B cell lymphoma
• CD52- alemtuzumab- also for B cell lymphoma

• They block the proteosome so cells can not degrade proteins.
• Inhibited by bortezomib
• Have activity in multiple Myeloma and mantle cell lymphoma

• Interferes with tumor cell replication
• Activity in melanoma, renal cell carcinoma, hairy cell leukemia, T cell lymphoma, and early stage CML
• Tox: predictable- flu like symptoms, myelosuppression, and hepatotoxicity.

• Increased expression of target proteins
• Increased DNA repair
• Failure of drug to enter cell or rapid efflux- mediated by MDR gene
• inability of drug to penetrate tumor- large tumors with hypoxic areas
• target proteins no longer available
• Target alteration
• Formation of trapping agent
• Decrease in activation of pro drug

• combination therapy
• dose intensity- give high doses killing the tumor before resistance can occur- does not work in ep tumors, only for leukemia and lymphoma
• Agents that reverse resistance.

• Chemotherapy given along with the primary therapy to increase cure rates.
• Used in treatment of early stage breast cancer, colon cancer, and osteosarcoma.
• Application of compertxian growth principles

• Attempt to induce complete response in sensitive tumors.
• Used in treatment of most acute leukemia, Hodgkin's disease, NHL, and testicular cancer
• Give high doese of several drugs, often requires a month and hematologic support

• Use of a higher dose of subsequent chemo to consolidate induced response and then maintain response with a lower dose.
• Used in acute leukemias
• usually given right after induction
• often need support with antibiotic prophylaxis

• Chemotherapy given before the primary therapy to reduce cell numbers making the primary treatment more effective.
• Used in advanced but local breast/rectal cancer
• typical drugs used in breast- FAC, FEC-100, Taxanes, A.I.s
• 5-FU + radiation in anal

• chemo with primary goal of improving quality of life, extending life is secondary.
• Used in most cancers
• - examples: glioma – temozolomide
• - head and neck – platinum
• - lung – gemcitabine
• - breast – vinorelbine
• - pancreas – gemcitabine
• - colon - capecitabine

• Alopecia
• Nausea and Vomiting
• Myelosuppression
• Mucositis
• Skin Changes

• It is predictable
• Commonly happens with anthracyclines, taxanes, and some alkylators
• usually 3 weeks after 1st cycle
• Hair still grows but is brittle
• When hair comes back it is often a different texture.
• Variation of drugs, avoidance of concurrent toxins

• Worse in young
• common with platinum, anthracyclines, IV nitrogen, Mustard derived alkylators
• psychologican component
• used to be main cause of premature discontinuation of chemo
• PRevent with light meals, amnesics, and multiple drugs
• use HT-3 inhibitors
• anti histaminics,
• Anti dopamines
• tranquilizers, steroids, and THC

• Very impt, biggest cause of death
• White count drops in 7-10 days, plates later, red cell drop 1%/day
• often get mucositis creating ideal infection environment.
• hygeine impt, avoid crowds, report fever or chills ASAP, broad spectrum antibiotics if fever with low absolute neutrophils
• consider fungal if fever persists
• give CSF after supsequent doses to support

• colony stimulating factors- granulocyteCSF used prophylactically, decreases infection related hospitalization/death but causes bone pain
• EPO- increases RBC

• usually seen with antimetabolites
• Usually at Nadir blood count
• Painful: dysphagia and diarrhea leading to malnutrition and electrolyte imbalance
• assoc with yeast infection big cause of sepsis
• give mouth care, pre chemo dental check
• good hydration, mouth wash with anesthetic
• ocassional feeding tube req

• leakage of IV drugs like alkylators from veins
• Antimetabolites can cause discoloration but not vesicles
• Nail changes- mainly taxanes
• Capecitabine- hand-foot syndrome
• acneiform rash common with targeted therapy like EGFR inhibitors and steroids

• if extravisation discontinue infusion
• elevate/ ice limb
• Give anti histamines and anti inflammatory agents
• keep close eye on pt for extention of of rxn
• consult plastics
• for hand-foot- reduce dose, gloves, skin emollients
• Acneiform rashes give topical antibiotics/steroids

• Common with Vinca Alkyloids, taxanes, and platinum.
• Sensory is the most common deficit- reversible
• Motor deficit usually late to show- usually irreversible
• Autonomic deficit- often GI constipation, unpredictable

• Common with anthracyclines, 5-FU, and high dose cyclyophosphamide
• Anthracycline- dose dep cardiomyopathy mediated by free radical intermediate. HT and radiation exacerbate, can be prevented with cardioprotective agent. herceptin can make it lethal
• 5-FU- unpredictable coronary spasm, seen with capecitabine as well
• cyclophosphamide is direct cardiac tox

• Monitor dose( anthracycline dep on cumulative dose)
• baseline and follow cardiac ejection fraction, drop>10%= discontinuation usually
• Avoid concurrent cardio tox like trastuzumab or radiation
• cardio protective agents

• common with cis- platinum, Mitomycin-C, and cyclophosphamide
• Cicplatinum is a dose dep prox tubule tox- can partially prevent with hydration and amifostine
• MitomycinC- can cause TTP w/renal failure, likely free radical mediated, unpredictable and irreversible
• Cyclophosphamide- acrolein mediated cystitis
• prevented with MESNA and hydration

• common with bleomycin, gemcitabine, busulfan
• Bleo- free radical intermediate interacts with heme assoc iron in pulmonary interstitium. Tox can be cumulative, must follow pulm function tests

• Common with all alkylators and anthracyclines
• Presents with myelodysplasia, myelofibrosis, leukemia, and ttp
• mediated by sub lethal DNA damage

• accelerated aging
• CNS- memory loss
• Fatigue- may be reversed with exercise and better sleep
• Chronic pain- less common- similar to fibromyalgia: possible response to better sleep, exercise, antidepressants, and neuropathic drugs
• Acceleration of osteoporosis, muscle loss
• secondary malignancies- leukemia, lymphoma, lung and bladder cancer common

• Variable, all agents increase risk of adverse outcomes in 1st trimester
• Should delay chemo if possible
• 2nd and 3rd trimester can use most agents except antimetabolites
• Need for chemo usually NOT an indication for abortion

• Cancer is thrombogenic
• aome antihormonal agents like tamoxifen are thrombogenic
• Chemo is less predictable regarding thrombosis
• 5-FU and Cisplatinum are vasoactive
• ALL pts high risk

• negative impact on libido, anxiety/depression
• Nausea, mucositis, fatigue
• dysfunction most common with anti hormonals like LHRH agonists, androgen/estrogen receptor block, and estrogen synth inhibitors

• corticosteroids, aromatase inhibitors, LHRH agonists, and most other chemo agents accelerate osteoporosis
• aromatase inhibitors and adjuvant chemo may cause arthralgias (primary reason for discontinuation of aromatase inhib)

• stop ovulation and azoospermia- common with alkylators and topoisomerase inhibitors- effects vary with age and sex
• Males- Hodgkins treated with MOPP usually sterile, testicular cancer treated with BEP often ok Should consider sperm bank

• alkylators caus anovulation- can recover usually if under 30yo
• premature menopause
• Maintain contraception
• Consider BCP during chemo
• consider HRT in non responsive tumors

• use the same carrier prtn as most chemo agents causing increase of relative dose of many
• can increase chemo induced mucositis
• increase bleeding risk

• use same carrier
• increase risk of fungal infection

• could inhibit drug activation- allopurinol inhibits 5-FU
• could increase drug effect- colchicine on vincas
• allopurinol on 6-MP

• increase risk of renal dysfunction like when using platinum
• HCTZ and cyclo/5-FU can cause prolonged neutropenia

decrease efficacy due to induction of liver metabolism with irinotecan

• warfarin and 5-FU/ capecitabine/ etoposide/ carboplatinum/ paclitaxel/ gemcitabine
• same carrier protein leading to increased bleeding