Anti-Neoplastic Agents

What is the difference between *primary & acquired resistance* in regards to neoplastic cell resistance to antineoplastic agents?

*Primary resistance* is thought to be due to the *genomic instability* associated with the development of most cancers *Acquired resistance* develops in *response to exposure to a given antineoplastic agent* -- Acquired resistance is *often highly specific to a single drug, or class of drugs*, and is usually based on a specific change in the genetic machinery of a given tumor cell with amplification or increased expression of one or more genes

What side affects of *bleomycin* results in the drug needing to be dose-limiting?

*Pulmonary toxicity* = this typically presents as pneumonitis w/ cough, dyspnea, dry inspiratory crackles & infiltrates on CXR. This drug can also cause *allergic reactions, fever, hypotension, skin toxicity, mucositis & alopecia*

Which tumors have a higher percentage of interior cells in the *Go Phase*?

*Solid Tumors*

What are the common adverse effects specific to *Cyclophosphamide* (alkylating agent, NITROGEN MUSTARD); how is this counter-acted?

*Sterile hemorrhagic cystitis* has been reported in 5-10% of patients treated with *cyclophosphamide* ---Attributed to the accumulation of the metabolite acrolein Can be reduced in intensity or prevented by the *parenteral administration of MESNA*, a sulfhydryl compound that reacts readily with and *neutralizes the effects of acrolein* in the acid environment of the urinary tract

Which drugs will work by *binding to beta-tubulin & promote microtubule formation & stabilization*?

*TAXANES* -*Paclitaxel* -*docetaxel*

Which *purine analog* can be taken *allopurinol*, so it is used as a substitute for *mercaptopurine* (6-MP)?

*Thioguanine* (6-TG) MOA: inhibits de novo purine nucleotide synthesis and DNA and RNA synthesis due to triphosphate incorporation

Which drugs will work by *binding to beta-tubulin & inhibiting microtubule assembly*?

*VINCA ALKALOIDS* -*Vinblastine* -*Vincristine*

WHich antineoplastic drugs are known as the *biological response modifiers*?

-- *Interferon-alfa* -- *Interleukin-2*

What is the *log cell kill hypothesis*?

---> *Destruction of cancer cells* by chemotherapeutic agents *follows first-order kinetics* (a given dose of drug destroys a constant fraction of cells rather than an absolute number per dose) Ex: A drug dose that would result in a *three-log cell kill* (i.e., 99.9% cytotoxicity) would *reduce the tumor burden from 10^12 cells (1 trillion) to 10^9 cells (1 million)* or from 10^5 cells to 10^2 cells

What are some *resistance pathways* which can be taken by neoplastic cells

(1) *Decreased drug transport* INTO cells (2) *Reduced drug affinity* due to mutations or alterations of the drug target (3) *Increased expression of an enzyme* that causes drug inactivation (4) *Increased expression of DNA repair enzymes* for drugs that damage DNA

What are the 5 main principles used when designing antineoplastic drug therapy?

(1) *Efficacy*: Each drug used in combination therapy should have some individual therapeutic activity and, if possible, should be used at the maximally tolerated individual dose (2) *Mechanism of interaction*: Drugs that act by different mechanisms may have additive or synergistic therapeutic effects, thus increasing log cell kill and diminishing the probability of the emergence of drug resistant tumor cells (3) *Toxicity*: Drugs with different dose-limiting toxicities should be used in combination to avoid cumulative damage to a single organ (agents with similar dose-limiting toxicities can be combined safely only by reducing the doses of each) (4) *Optimum scheduling*: Intensive intermittent schedules of drug treatment should allow the shortest time required for recovery of most sensitive target tissue (usually bone marrow) from the acute toxic effects of antineoplastic agents (5) *Repeated exposure*: Several cycles of treatment should be given (most curable tumors require at least 6-8 cycles of therapy)

What side effects are more specific to *Cisplatin* (alkylyating agent, PLATINUM coordination complex)?

(1) *Nephrotoxicity* is a common adverse effect of cisplatin (can be overcome by the routine use of hydration and diuresis during therapy) (2) *Ototoxicity* caused by cisplatin is unaffected by diuresis and is manifested by tinnitus and hearing loss in the high-frequency range --- Ototoxicity can be *unilateral or bilateral*, tends to be more frequent and severe with repeated doses, and may be more pronounced in children (3) Other adverse effects that commonly occur with cisplatin treatment include *marked nausea and vomiting* (can be controlled with ondansetron and high dose corticosteroids)

List the advantages of *Combination Drug chemotherapy*

(1) Provides *maximal cell killing* within the range of *tolerated toxicity* (2) *Effective against a broader range of clones* with different genetic abnormalities in a heterogeneous tumor population (3) May *delay or prevent the development of drug-resistant tumors*

COmpare acute & delayed toxicities of *Alkylating agents*.

*Acute toxicity* = *NAUSEA and VOMITING* occurs within *30-60 min of IV administration* (pretreatment with a serotonin (5-HT3) receptor antagonist (e.g, ondansetron) can ameliorate emetogenic effects) *Delayed toxicities* include MYELOSUPPRESSION with *leukopenia, thrombocytopenia, nephrotoxicity, alopecia, mucosal ulceration, and intestinal denudation* These drugs also have a high prevalence of tissue damage at the site of administration

Which anti-neeoplastic drug classes are considered *cell-cycle non-specific (CCNS)*?

*Aklylating Agents* *Anthracyclines* *Anti-tumor Antibiotics* *Platinum Analogs*

WHat are adverse side affects associated with *fluorouracil (5-FU)*?

*Anorexia* *Nausea* *Stomatitis* *Diarrhea*

Which anti-neoplastic drug classes are considered *cell cycle specific (CCS)*?

*Antimetabolites* Taxanes (M phase) Vinca Alkaloids (M phase) Topoisomerase I or II Inhibitors *Anti-tumor Antibiotics*

WHat are the DDIs to be aware of with the administration of *methotrexate* (MTX)?

*Aspirin & other nonsteroidal anti-inflammatory agents* *Penicillin* & *Cephalosporins* inhibit renal excretion of MTX

Both metastatic cancers and antineoplastic agents can have skeletal bone complications which can increase the incidence of fractures & bone pain --- what can be given to try to prevent these complications?

*BISPHOSPHONATES*, are available to *inhibit osteoclast action and bone resorption* and may be used to delay the time to the first skeletal complication

What is a *proteasome inhibitor* which can be used as a anti-neoplastic agent?

*Bortezomib*

Which *alkylating agent* is known to specifically cause *hyperpigmentation, pulmonary fibrosis & adrenal insufficiency*?

*Busulfan* (Aklyl sulfonate)

Is *mercaptopurine* (6-MP) a CCS or CCNS drug?

*CCS* -- to cells that are in *S-phase*

Which cancer treatment approach is seen in all clinical setting treatments with Induction, Neoadjuvant, & Adjucant Therapies?

*Chemotherapy*

What are the common routes of administration for antineoplastic agents?

*Common routes include IV and PO* >> Alternative routes are used to reduce systemic toxicity and to increase drug delivery by avoiding pharmacologic sanctuaries Example: intraarterial perfusion of antineoplastic agents through a catheter implanted in the hepatic artery can be used in patients with metastatic carcinoma of the liver and little or no disease elsewhere (a common occurrence in colorectal cancer) >> Intracavity, intrathecal, intraventricular, and topical routes of drug administration are also used in specific cases

What event occurs in *S phase*?

*DNA Synthesis* - this is the replication of DNA genomes.

What are the main *Protein tyrosine-kinase Inhibitors* which are used as anti-neoplastic agents?

*Dasatinib* *Erlotinib* Gefitinib *Imatinib* *Lapatinib* Nilotinib Sorafenib Sunitinib

Which is going to have a *higher growth fraction*; a solid or a disseminated tumor?

*Disseminated tumor* will have a higher growth fraction. Solid tumors have a lower fraction because they have inadequate nutrient supply to the interior of the tumor.

Which antineoplastic agent may cause a patients urine to turn *red* (but this is NOT hematuria)?

*Doxorubicin* (or other anthracycline antibiotics) --Other SAs include: nausea, vomiting, alopecia, myelosuppression, *stomatitis*, & *cardiotoxicity* (long-term SA, due to free radicals)

There are antitumor antibiotics which are known as the *anthracyclines* -- What are they and what are the 4 main effects of their MOA?

*Doxorubicin*, Daunorubicin, idarubicine, epirubicine. MOA: 1. *Inhibits topoisomerase II* 2. *Intercalates DNA* and blocks synthesis of DNA and RNA and blocks DNA strand scission 3. *Generates semiquinone* and oxygen free radicals 4. *Binds to cellular membranes* to alter fluidity and ion transport

What agents might you need to give to a patient in order to minimize the adverse effects of from a *anti-neoplastic agents*?

*Erythropoietin* or darbepoetin *Filgrastim* and pegfilgrastin Oprelvekin Sargramostim Serotonin antagonists (*Ondansetron*)

What is the *most widely used agent* in *colorectal cancer*?

*Fluorouracil (5-FU)*

What are some common *Pyramidine analogs* (antimetabolites)?

*Fluorouracil (5-FU)* Capecitabine Cytarabine (Ara-C)

Which antineoplastic agent works by *active compound* of the drug *covalently binds thymidylate synthetase& and blocks de novo synthesis of thymidylate?

*Fluorouracil (5-FU)* --> 5-FU is a PROdrug and the active compound of the drug are *FdUMP* Other active compounds *FdUTP & FUTP* will be incorporated into both DNA and RNA, respectively, interfering with DNA synthesis, DNA function, RNA processing, and mRNA translation

What phase of the normal cell cycle *precedes DNA synthesis* & is where the cell synthesizes components necessary for DNA synthesis?

*G1 Phase* -TYpically the synthesis of cellular components needed for DNA synthesis.

In what phase is there *synthesis of components for *mitosis* (cell division)?

*G2 Phase*

WHich antineoplastic agent can have a delayed toxicity which results in *increased risk of clotting & bleeding*, *pancreatitis* & CNS toxicity including lethargy, confusion, hallucinations & coma?

*L-asparginase* (Enzyme for antineoplastic treatment) Can also result in an acute hypersensitivity reaction (fever, chills, nausea, vomiting, skin rash, urticaria).

What is the *major limiting factor* in the effectiveness of *chemotherapy of cancer*? Explain this factor.

*Lack of SELECTIVE TOXICITY* Since antineoplastic agents target cells that are highly proliferative (high growth fraction), *rapidly proliferating normal tissues are the major sites of toxicity of these agents* (high growth fraction tissues include bone marrow, gastrointestinal tract, hair follicles, buccal mucosa, and sperm forming cells) Toxicities affecting the heart, lungs, or kidneys may be irreversible if not detected early

How exactly is *Leucovorin* beneficial in combination with *high dose therapy of methotrexate*?

*Leucovorin is able to compete with free MTX for binding to DHFR* in NORMAL cells; in *TUMOR* cells, MTX is metabolized to MTX polyglumates *(PGMTX)*, which is critical for the therapeutic action of MTX; *leucovorin CANNOT compete with PGMTX for DHFR binding* = rendering tumor cells more sensitive to MTX than normal cells

What are the drugs known as *rescue agents* for anti-neoplastic treatment?

*Leucovorin* *Mesna*

In what cell cycle phase does the cell divide into *two daughter G1 cells*? What is the route that can be taken by each of these daughter cells?

*M-Phase* - Each daughter cell may *re-enter the cell cycle* or *pass into a nonproliferative stage (Go)*

Which drug is a commonly used *Folic Acid Analog* (antimetabolites)? What is its MOA?

*Methotrexate (MTX)* MOA = *Inhibits dihydrofolate reductase (DHFR) and blocks conversion of folic acid to tetrahydrofolic acid*, which serves as the key one-carbon carrier for enzymatic processes involved in the de novo synthesis of thymidylate, purine nucleotides, and the amino acids serine and methionine -- Varied Low dose and High dose therapy

What might arise more than 10 years after cancer treatment?

*Most antineoplastic agents are mutagens themselves*, and *neoplasms may arise ten or more years after the original cancer was cured* (e.g., acute myeloid leukemia) >> Treatment-induced tumors can occur after therapy with alkylating agents

What type of cancer therapy is given as a *first step to SHRINK a tumor before the primary treatment* (usually surgery) is given? What are some examples procedures for this kind of therapy?

*NEOADJUVANT Therapy* Ex: chemotherapy, radiation therapy & hormone therapy (can be type of induction therapy)

Which major type of *Alkylating agent* has a slightly different mechanism of action than the other major types?

*PLATINUM* compounds do NOT alkylate DNA, but they are included under alkylating agents because they *form covalent bonds with DNA* like other alkylating agents

Hypersensitivity reactions are relatively common in which *taxane* agent?

*Paclitaxel* = This reaction can be prevented by either premedication w/ *dexamethasone, diphenhydramine & an H2 blocker, or by substituting albumin-bound paclitaxel.

What are the 3 different categories of *Anti-metabolites* which can be used as *Anti-neoplastic agents*?

1. *Folic acid analogs* (*methotrexate*, pemetrexed) 2. *Pyrimidine analogs* (flucapecitabine, cytarabine, *fluorouracil*, gemcitabine) 3. *Purine analogs* (clofarabine, fludarabine, *Mercaptopurine*, nelarabine)

What are the three terms for cancer treatment depending on the *timing of that therapy*?

1. *Induction Therapy* 2. *Neoadjuvant Therapy* 3. *Adjuvant Therapy*

Describe the adverse effects associated *vinblastine & vincristine*.

Adverse effects include: *hair loss* *local cellulitis* if extravasated *myelosuppression* occurs to a greater extent with vinblastine while vincristine causes more predictable, cumulative neurological toxicities (e.g., numbness and tingling of the extremities and loss of deep tendon reflexes, followed by motor weakness)

List the commonly used *monoclonal antibodies* which are used as anti-neoplastic agents.

Alemtuzumab *Bevacizumab* *Cetuximab* Gemtuzumab Ibritumomab *Rituximab* Tositumomab *Trastuzumab*

Which mutation is associated with a higher frequency for *multidrug-resistant phenotype* which can occur in some neoplastic cells?

THis type of resistance is associated with an *increased expression of the MDR1 gene* which encodes a cell surface transporter glycoprotein (P-glycoprotein). = P-glycoprotein pump is an *ATP-dependent transporter* that confers resistance to anthracyclines, vinca alkaloids, etoposide, paclitaxel, dactinomycin & others.

*Vinblastine & Vincristine* are cell-cycle specific drugs which target what?

Target cells that are in the *M phase*.

What is *induction therapy* for cancer treatment? Often when used by itself, is it effective?

The *first treatment given*. It is often part of a standard set of treatments, such as *surgery followed by chemotherapy and radiation*. = When used by itself, *induction therapy is the one accepted as the BEST treatment*. If it doesn't cure the disease or it causes severe side effects, other treatment(s) may be added or used instead. It is also called *first-line therapy, primary therapy, and primary treatment*.

If anti-neoplastic drugs work best on tumors which have a high growth fraction, that how can we increase the growth fraction of a *slow-growing solid tumor*?

The growth fraction of slow-growing solid tumors can be *increased by reducing the tumor burden through surgery or radiation*, which promotes the recruitment of some of the *remaining cells into active proliferation* and *increases their susceptibility to chemotherapeutic agents*

Describe the growth rate in most *solid tumors*.

The growth rate of most solid tumors in vivo is *initially rapid, but growth rate decreases as the tumor size increases* > *Decrease in growth rate is due to the unavailability of nutrients and oxygen* caused by *inadequate vascularization* in solid tumors (e.g., colon cancer) compared to disseminated tumors (e.g., leukemias)

*Cancer* is a disease characterized by uncontrolled multiplication & spread of abnormal forms of the body's own cell -- what is the common cause of that uncontrolled multiplication & spread?

The invasive and metastatic nature of neoplastic cells, in combination with their genetic instability, produces symptoms and eventual death illustrated by the *loss of normal control mechanisms that govern cell survival, proliferation, and differentiation* (often termed genetic instability). This *genetic instability* found within cancer cells can also *lead to selection of more survivable clones* through resistance to chemotherapy and radiotherapy. of the patient unless the neoplasm can be eradicated with treatment.

What is the major limiting factor in chemotherapy?

The level of *cytotoxicity normal tissues*. ONLY a limited log cell kill can be expected w/ each individual treatment (otherwise there is an increased risk of adverse events to the patient)

What are the *goals* of *cancer treatment* (specifically chemotherapy)?

The ultimate goal of chemotherapy is to produce 100% kill of cancer cells while *causing limited injury to normal tissues* >> A true cure requires the eradication of every neoplastic cell >> If a cure is not attainable, then the goal becomes palliation, which allows the patient to maintain a 'normal' existence

Are alkylating agents *CCS or CCNS*?

These agents are *Cell Cycle NON-specific (CCNS)* But for these agents, cells in the *G1 & S phases are MOST susceptible*

What are the phases of the *cell cycle*? (in a normal cell)

Cell Cycle: consists of a definable sequence of events that characterize the growth and division of cells and can be observed by morphological and biochemical means (differences in duration of the cell cycle occur b/w cell of various types, ALL cells display a similar pattern during the division process. *G1 Phase* (precedes DNA synthesis) *S-Phase* (DNA synthesis) *G2 Phase* (synthesis of components for cell division) *M-Phase* (cell divides into two daughter G1 cells)

The *pyrimidine analog, Fluorouracil (5-FU)* is cell cycle specific (CCS) to what?

Cells in the *S-phase*.

What is the reasoning behind using *combination therapy* in cancer treatment?

Combination of *surgical excision, irradiation and chemotherapy treatments* is KEY to proper cancer treatment because: < 10% of advanced stage tumors are able to be cured using chemotherapy alone while *up to 50% of cancer patients can be cured w/ combinatorial treatment methods*

The transition in the cell cycle is tightly controlled by the activity of what molecules?? How are these molecules activated & inhibited?

Each transition in the cell cycle is tightly controlled by the activity of *specific cyclin-dependent kinases (CDKs)* >> *activated by* small regulatory proteins called *cyclins* >> *inhibited by* other proteins, such as *p16 and p53* (tumor suppressors)

Patients on *alkylating agents* will need frequent monitoring for what?

Frequent monitoring of *blood counts* is essential during administration of these agents due to the *possible development of severe leukopenia or thrombocytopenia* (may necessitate discontinuation of therapy)

*Growth fraction* is what value? (used in tumor growth rate calculations)

Growth Fraction = *ratio of proliferating cells to cells in the Go stage* Proliferating Cells:Go cells

What is a common side effect of *male patients on chemotherapy*?

They will likely have a *low sperm count* because of the chemotherapy agent targeting highly proliferative cells.

*Antineoplastic agents* work best on tumor with a high or low growth fraction? Which tumors are example of the effectiveness of this therapy?

They work BEST on a a tumor with a *HIGH growth fraction* *Burkitt lymphoma & Trophoblastic choriocarcinoma* has growth fractions which are close to 100% so they are readily curable with a single agent chemotherapy.

The Co-administration of what other drug can increase levels of *mercaptopurine* (6-MP) in a patient and may result in *increased 6-MP toxicity*?

This can occur if there is simultaneous administration of *Allopurinol* w/ oral 6-MP. So if they must be co-administered than the physician will need to reduce the oral dose of 6-MP to 50-75%. (IV dose would be UNaffected)

*L-asparginase* will work on what tumors?

This enzyme will hydrolyze circulating L-asparagine into aspartic acid & ammonia, effectively inhibiting protein synthesis. Work well with *Acute lymphoblastic leukemia* tumor cells b/c they lack the enzyme aspargine synthetase so they vulnerable to this enzyme.

The *high toxicity* associated with each drug leads to what characteristic of antineoplastic agents? What are the common symptoms of this toxicity?

This is what causes the *NARROW therapeutic index* = *severe vomiting, nausea, stomatitis, and alopecia* (loss of hair) occur to a lesser or greater extent during therapy with nearly all antineoplastic agents

*Etoposide* (a epipodophyllotoxins) will target cells in what phase?

This will block cell division in the *late S-G2 phase*

With the cell cycle of a *tumor cell*, how is that different from that of a normal cell?

Tumor Cell Cycle = mirrors that of normal cells except that *proteins or pathways involved in the cell cycle checkpoints* are often *absent or mutated* = *altered RATE of activity* Aberrations in checkpoint regulation result in *uncontrolled and unregulated cell proliferation*, a central quality of cancer cells

What are the major drug classes used in *antineoplastic therapy*?

1) *Alkylating Agents* 2) *Antimetabolites* 3) Natural Products 4) *Hormones & Antagonists* 5) MIscellaneous Agents 6) *Monoclonal Antibodies* 7) *Vaccines* 8) *Rescue Agents* 9) Agents used to minimize adverse effects.

What are some factors/medications which can be given to cancer patients to *minimize adverse effects*?

1) The *granulocyte-macrophage colony-stimulating (GM-CSF) factor sargramostim* and the granulocyte colony-stimulating *factors (G-CSF) FILGRASTIM and pegfilgrastin* can stimulate production of *WBCs* and shorten the length of neutropenia 2) The platelet growth factor *oprelvekin* is used to counteract *thrombocytopenia* 3) Anemia can be treated with *ERYTHROPOIETIN or darbepoetin*, factors that stimulate *RBC production*

What are the two categories which can be used to classify *chemotherapeutic drugs*?

1. *Cell Cycle Specific (CCS)* are agents that are anti-neoplastic agents which are cytotoxic for cells during specific phases of the cell cycle. 2. *Cell Cycle Non-Specific (CCNS)* are agents that are anti-neoplastic agents that are cytotoxic regardless of whether the cells are cycling or resting in the Go compartment.

What is the MOA of *Bleomycin* (antitumor antibiotic)? How is this CCS?

MOA: *small peptide that binds to DNA resulting in single- and double-strand breaks* and also inhibits DNA biosynthesis This antibiotic is cell cycle specific for *G2 phase*

*Methotrexate* (MTX) are *cell cycle specific* (CCS) for what?

MTX will target cells in the *S-phase*

WHat can result from the *myelosuppression* which is sometimes a chemotherapy-drug induced side effect? At what point in treatment is this suppression usually seen?

Myelosuppression can lead to: *leukopenia* *thrombocytopenia* anema (lesser extent) (a) Blood counts normally reach their nadir (low point) *10-14 days after treatment with recovery by day 21* and a return to normal by day 28 (b) Most regimens are given in cycles of 21-28 days (c) Some agents (e.g., nitrosoureas) involve a longer period of recovery and are often administered every 6 weeks

What is one of the greatest challenges to *antineoplastic therapy*? How does this affect the monitoring of different functions during treatment?

One of the greatest challenges to antineoplastic therapy is *adjusting the dose to achieve a therapeutic, but nontoxic, outcome* Because Antineoplastic drugs harm not only neoplastic tissues, but also healthy tissues as well Numerous factors must be considered, such as *renal and hepatic function, bone marrow reserve, general performance status*, and *concurrent medical problems* Less quantifiable factors include the patient's willingness to undergo potentially dangerous treatments, the patient's physical and emotional tolerance for side effects, and the likely long-term gains and risks involved

What are the two different *schedules of Administration* for chemotherapy? Which form is most common and when would you use it?

1. *Intermittent high-dose therapy* = *most common form* of anticancer agent administration --> *Allows recovery of normal tissues* (e.g., the patient's immune system), also affected by antineoplastic agents, and *reduces the risk of serious infection* --> May be more effective with agents that are phase nonspecific (cell cycle nonspecific) 2. *Continuous infusion* --> Drugs that are *rapidly metabolized or excreted (or both) appear to be more effective when administered by continuous infusion* --> *Antineoplastic agents that act only on one portion of the cell cycle* (cell cycle specific) are also often more effective when administered by continuous infusion

What are the main problems associated with *chemotherapy*?

1. *Resistance* (which includes potential for multidrug resistance) 2. *Toxicity*

What are the three main approaches to *treating established cancer*?

1. *Surgical Excision* 2. *Irradiation* 3. *Chemotherapy*: Historically, cancer treatment has used cytocidal antineoplastic agents to cause lethal cytotoxicity (e.g., cell lysis). Current treatments now include agents that are also cytostatic (suppress cell growth and multiplication but do not kill cells) >> **Combination of these treatment strategies are KEY*, as < 10% of advanced stage tumors are able to be cured using chemotherapy alone while up to 50% of cancer patients can be cured with combinatorial treatment methods

What are two common examples of the issues that can be seen in the *checkpoints* of a *tumor cell cycle*?

1. *p53 gene product is mutated or absent* - this will result in a checkpoint failure where cells with damaged DNA will NOT be diverted to apoptotic pathways, but will proceed through S-phase. -Cells can then emerge mutated and become a resistant population. 2. *Mutated CDKs* which leads to *hyperactive proteins* --> *relentless proliferation of tumor cells*

What are the two categories for *antimitotic drugs* (natural antineoplastic agents)?

1. *vinca alkaloids* (vinblastine & vincristine) 2. *Taxanes* (paclitaxel & docetaxel)

What are the two main indications for *antineoplastic chemotherapy*?

1. Antineoplastic chemotherapy is often indicated when *neoplasms are disseminated* and are *not amenable to surgery* 2. Chemotherapy is also used as a *supplemental treatment to attack micrometastases following surgery and radiation* (may be indicated in cancers without preceding surgery or radiation treatment)

WHat is the mechanism of action for *Mercaptopurine (6-MP)*? This is a Purine analog which is an antimetabolite agent.

6-MP = *inhibits de novo purine nucleotide synthesis* & *DNA and RNA synthesis* due to triphosphate incorporation.

What is a *Pharmacologic Sanctuary*? What may need to be done if one exists?

= *Regions where tumor cells are less susceptible to antineoplastic agents* Ex: include the interior of solid tumors or specific tissues (e.g., CNS, testes) where transport constraints prevent certain chemotherapeutic drugs from entering and have been a major cause of treatment failure (e.g., acute lymphocytic leukemia in children) In cases where pharmacologic sanctuaries exist, a *patient may require localized irradiation* (e.g., of the craniospinal axis) or *intrathecal administration of drugs to enter the CNS* Alternatively, *surgical resection of solid tumors may induce any remaining cells to enter into the cell cycle*, causing them to become more susceptible to various antineoplastic agents

What is the general *mechanism of action* of *Alkylating Agents*?

= Alkylating agents are *strong electrophiles* and exert their cytotoxic effects by *forming covalent linkages with DNA* --> Alkylation of DNA leads to *intra- and inter-strand cross-linking*, which *prevents the tumor from unwinding DNA for mRNA production or DNA replication( --> Alkylation of DNA (particularly guanine bases) can also lead to *miscoding* through abnormal base pairing with thymine or in depurination by excision of guanine residues, which *leads to DNA strand breakage* --> Cross-linking of DNA is a major cause of the cytotoxic action of alkylating agents and replicating cells are most susceptible to these agents

*Primary induction chemotherapy* is the drug therapy that is administered at what point of care? What are the goals of this treatment?

= Drug therapy administered as the *primary treatment in patients who present with advanced cancer* for which *no alternative treatment exists* Goals of therapy are to palliate tumor-related symptoms, improve overall quality of life, and prolong time to tumor progression Improves surcical relative to supportive care in patients w/ a variety of solid tumors.

What is a *Differentiating Agent* that is commonly used as a antineoplastic agent?

>> Differentiating agents Arsenic trioxide Histone deacetylase inhibitor (vorinostat) *Tretinoin*

How can the SAs of *nausea & Vomiting* be minimized?

>> Promethiazines: promethazine, prochlorperazine, chlorpromazine >> *Serotonin antagonists: ONDANSETRON*, granisetron, dolasetron, palonosetron >> Cannabinoids: dronabinol, nabilone >> Benzodiazepines: lorazepam >> Corticosteroids: dexamethasone

What is *adjuvant therapy* for cancer treatment? how is this commonly carried out?

Adjuvant therapy = *Additional cancer treatment given AFTER the primary treatment to lower the risk that the cancer will come back*. Can include *chemotherapy, radiation therapy, hormone therapy, targeted therapy* (designed to identify and attack specific types of cancer cells with less harm to normal cells), or *biologic therapy* (treatment that uses substances made from living organisms).

What are the adverse effects which are associated with the *taxanes* (paclitaxel & docetaxel)?

Adverse effects include: *bone marrow depression* *peripheral sensory neuropathy* (paclitaxel) *neurotoxicity, fluid retention, and neutropenia* (docetaxel)

Compare the use of *methotrexate* (MTX) at low-dose vs. high-dose therapy.

At *LOW doses, MTX is actively transported into the cell by membrane proteins* and is *LESS harmful* on healthy tissues (common in the *Tx of rheumatoid arthritis, colitis, psoriasis*, and some cancers) *High-dose MTX therapy*, where methotrexate *enters healthy cells by diffusion* across the concentration gradient, *causes injury to healthy tissues* = *Leucovorin* (folinic acid) must be administered to 'rescue' these healthy tissues.

There is a small subset of patients with advanced disease that may be cured with *primary induction chemotherapy* -- what are these diseases?

In ADULTS: Hodgkin and non-Hodgkin lymphoma acute myelogenous leukemia germ cell cancer choriocarcinoma In CHILDREN: Acute lymphoblastic leukemia Burkitt lymphoma Wilms' tumor embryonal rhabdomyosarcoma

What are the antineoplastic drugs which are considered *immunomodulators*?

Lenalidomide *Thalidomide*

What is the MOA for *Tretinoin* (antineoplastic agents)?

MOA: *binds to one or more nuclear receptors* (retinoic acid receptor-α) and *induces clonal proliferation and/or granulocyte differentiation*

What is the MOA for *etoposide*?

MOA: *inhibit topoisomerase II*; leads to DNA damage through strand breakage induced by the formation of a ternary complex of drug, DNA, and enzyme SAs for this drug are common ones for all antineoplastic agents (alopecia, nausea, vomiting, & myelosuppression)

Why would you use *neoadjuvant chemotherapy* on a patient with a *localized cancer*?

You would use this type of chemotherapy on a localized cancer for which *alternative local therapies (surgery, radiation) exist but for which they are less than completely effective* Ex: anal, gastroesophageal, laryngeal, and non-small cell lung cancer includes chemotherapy and radiation administered either concurrently or sequentially

What are the 5 majore types of *alkylating agents* which are used as *antineoplastic agents*?

a) *NITROGEN MUSTARDS* Chlorambucil *Cyclophosphamide* *Ifosfamide* Mechlorethamine Melphalan b) *METHYLHYDRAZINE* Derivative Procarbazine c) *ALKYL SULFONATE* *Busulfan* d) Nitrosoureas Bendamustine Carmustine Streptozocin e) Triazenes Dacarbazine Temozolomide f) *PLATINUM* coordination complexes Carboplatin *Cisplatin* Oxaliplatin

What are the *Natural products* which can be used as an *Antineoplastic agents*?

a) VINCA ALKALOIDS *Vinblastine* *Vincristine* Vinorelbine b) TAXANES Docetaxel *Paclitaxel* c) EPIPODOPHYLLOTOXINS *Etoposide* Teniposide d) Camptothecins Irinotecan Topotecan e) Antibiotics *Bleomycin* Dactinomycin (actinomycin D) Daunorubicin *Doxorubicin* Mitomycin C Mitoxantrone f) ENZYMES *L-Asparaginase* Pegaspargase