Cancer Chemotherapy

Review: Ch. 52 Goodman & Gilman

What is Cancer?

Disease of Cells

Lack control mechanisms (feedback) Chromosomal abnormalities

bcl-2 oncogene (apoptosis suppressor) p53 gene (tumor suppressor turned oncogene)

Tumor stem cells (small population) Cellular Immortality (telomerase) Metastases (travel to distant sites) Clonogenic (colony forming ability)

Common Cancer lingo

MAIN

Carcinoma epithelial origin Sarcoma connective or muscle origin Lymphoma Lymphatic tissue

Hodgkins distinctive cell type Acute/Chronic Myelogenous abnormal appearing WBC Lymphocytic High lymphoblast # (young WBC)

Leukemia hematopoetic origin

Myeloma muscle tissue Neuroblastoma solid tumor: adrenal gland Melanoma skin pigment cells

Risk Factors

Age Sex Ethnicity Environment Lifestyle Infections Genetics Medications

Treatment Options

Surgery solid tumors Radiation solid tumors

Chemotherapy

Hormonal Therapy Biological Response Modifiers

Gene Therapy BMT Supportive Therapy (Other drugs)

Modalities of Chemotherapy

Curative

Childhood leukemia, osteogenic sarcoma, lymphoma, testicular, Wilm tumor & Ewings sarcoma Improve survival neuroblastoma, adult leukemia, myeloma, lymphoma, breast, stomach, ovarian, endometrial, uterine cancers Palliate symptoms CLL, CML, prostatic, colon, head & neck, aggressive lymphomas Breast, ovarian, colon Osteosarcoma, rectal, head & neck Tamoxifen, ASA, folic acid, sunscreen, lead suits?

Palliative

Adjuvent follow surgery/radiation

Neoadjuvent prior to surgery

Prevention

How to Target Cancer Cells?

Exploit properties unique to Cancer cells

The Growth Factor (Fraction)

Major determinant of chemotherapy effectiveness Defined: Proliferating:Resting cell ratio Related to the Cell Cycle

Enzyme production Vascularization

The Cell Cycle (flashback)

Drug Targets

Chemotherapy drugs are more toxic to tissue with high growth fraction High fraction = rapidly growing

Disseminated cancers Solid tumors

Low fraction = slow growing

Obstacles to Chemotherapy

Healthy High Growth Fraction Areas

Bone marrow Skin Hair follicles Sperm Gastrointestinal tract

Poor selectivity of drugs Healthy and cancerous cells affected

Toxicity is Dose Limiting

Toxicity Roadmap - handout

Major Toxicities

Bone Marrow Suppression

Neutropenia Low WBC

Thrombocytopenia Low platelete count

G-CSF (filgrastim) & GM-CSF (sargramostim) Oprelvekin (Neumega)

Anemia Low RBC

Digestive Tract Problems

http://www.medscape.com/mp/rc/anemia Erythropoetin

Nausea & Vomiting (N/V)

Stomatitis inflammation of oral mucosa Diarrhea impaired nutrient absorption Occurs 17 98% (Psych factors) Ondansetron (Zofran) and others (handout)

Major Toxicities cont

Other

Alopecia hair loss Reproductive sterility in males Hyperuricemia increased urination (DNA) Extravasation of vesicants Drug-specific (hepatic, coronary, etc) Carcinogenesis some patients sensitive

Obstacles cont

Cure requires 100% cancer cell death Nearly impossible!

Kinetic problems (drugs are 1st order) Nonparticipation of immune system Treatment duration? Patient has 1012 cancer cells systemically Treatment kills 99.999% Patient still has 107 cancer cells

Example

Obstacles:Detection vs. Prognosis

Absence of Early Detection

Only cervical cancer is detectable early Consequences of late detection

Metastases Decreased responsiveness to Chemo

Solid tumors respond poorly Drug resistance Tumor Cell Heterogeneity Limited Access (diffusion, transport, etc.)

Patient debilitation

Resistance Mechanisms

Often produced by the drug itself (mutagen) Cellular adaptation altered enzyme levels

Example: Methotrexate increased dihydrofolate reductase produced to overwhelm drug

Reduced drug transport into cells Reduced molecular target affinity Stimulation of alternative biosynthetic pathways Impaired activation or increased metabolism Cellular repair mechanisms for DNA

Example: repair of crosslinks or scission caused by alkylating agents

Drug efflux pumps become overexpressed

Multiple Drug Resistance P-glycoprotein

Anticancer Drug Resistance

Primary

Absence of a first response Non-small cell lung & colon cancers

Increased expression of MDR1 Creates more surface glycoprotein Uses ATP to expel a variety of molecules

Acquired

Resistance cont

Multidrug Resistance

Due to Increased expression of pumps Affected Drugs

Antibiotics Vinca alkaloids No common mechanism of action!

Surprising cross-resistance!

Chemo Strategies

Intermittent chemotherapy Combination chemotherapy Regional drug delivery Intra-arterial solid tumors Intrathecal CNS delivery (non-BBB drugs) Intracavity pleural, peritoneal, bladder Portal Vein Liver Brain Implants

Chemo Strategies cont

Intermittent Chemotherapy

Chemo Strategies cont

Combination Chemotherapy

Suppression of Drug Resistance Increased Cancer kill rates Reduced systemic toxicity Selection Criteria

Each drug effective alone Different mechanism of action Minimal overlapping toxicities

Combination Chemotherapy

Cytotoxic Drugs

Classes Alkylating agents Antimetabolites Antitumor antibiotics Mitotic inhibitors Topoisomerase inhibitors Other

Cytotoxic Drugs cont

Disrupt DNA synthesis Block mitosis Disrupt protein synthesis Target cell replication

High Growth Fraction most affected

Cell cycle specific vs. nonspecific

Cell Cycle Specific Drugs

Toxic to cells in a specific phase

Vincristine - causes mitotic arrest

Only effective in M-Phase Prolonged infusions Multiple doses

Require long presence

Known as Schedule Dependent Drugs Classes

Antimetabolites (S) Mitotic Inhibitors (M) Asparaginase (G1 & S) Bleomycin (G2) Etoposide (G2)

The Cell Cycle (flashback)

Cell Cycle Nonspecific Drugs

Act during any phase (even G0) Synergistic w/cell cycle specific drugs More toxic to proliferating cells

Cells use G0 for repair Toxicity apparent during proliferation Alkylating Agents Most antitumor antibiotics

Include

I. Alkylating Agents

Cells are killed by the alkylation of DNA

Formation of a covalent bond between drug and DNA (usually N7 on G) to form crosslinks Methylation at N7

Procarbazine, streptozocin, dacarbazine, temozolomide

Mono vs. Bifunctional alkylating agents Cell cycle nonspecific agents Drug resistance is common Adverse effects Occur in high growth faction tissues

Alkylating Agents

Results in miscoding or breaking of DNA Inhibits DNA replication Cells most susceptible during S and G1 Can be given in a single bolus Resistance

Repair enzymes Anti-porters Increased metabolism (CYP) Increased nucleophile production: glutathione

Most are vesicants (tissue blistering)

Chemical Warfare circa 1914

Two most common agents: Chlorine gas Mustard gas

S Cl Cl

Mustard Gas!

R
N Cl Cl

Nitrogen Mustard

MOA: Nitrogen Mustards

Generation of highly reactive aziridinium ions that act as alkylating agents to cross-link DNA producing defective DNA and abnormal cellular function and eventually cell death
Cl N Cl CO2H

CO2H N + Cl

Chlorambucil - Leukeran

Actual alkylating species: An aziridine

Indications: leukemias (DOC for CLL) and lymphomas. Can be given P.O. Bi-functional, 99% plasma protein bound, extensive hepatic metabolism to active metabolites Least toxic of the nitrogen mustard agents - conduct weekly blood counts Warning: severely suppress bone-marrow function (neutropenia/myelosupression), known carcinogen in humans, mutagenic and teratogenic - USE contraception!!

Crosslinking

Nitrogen Mustards
H N O P N O Cl Cl

R
N Cl Cl

Indications: MANY: Malignant lymphomas, mycosis fungoides and leukemias; several nonmalignant diseases: severe rheumatoid arthritis and systemic lupus erythematosus Prodrug: requires CYP450 for activation Cardiotoxicity possible, immunosuppressive, preferably take on an empty stomach, USE contraception Non-vesicant!

Cyclophosphamide - Cytoxan, Neosar

acrolein

Cl
N H O P N O Cl

Indications: Germ cell testicular cancer

Urotoxic side effects hemorrhagic cystitis, CNS problems such as confusion and coma
Prodrug: requires CYP450 for activation Powder for injection obtain a urinalysis prior to each dose, USE contraception

Ifosfamide - Ifex

BOTH of these agents can cause hemorrhagic cystitis - Mesna

Nitrogen Mustards
Cl H 3C N Cl

R
N Cl Cl

HCl

Indications: Hodgkins disease, lymphosarcoma, lymphocytic leukemia, mycosis fungoides, metastatic disease via intrapleural, intraperitoneal or intrapericardial administration Extravasation a problem 0.16 M sodium thiosulfate and ice packs, highly reactive aziridinium ion Injection only, monitor renal, hepatic and bone marrow

Mechlorethamine HCl - Mustargen

MOST reactive of the mustards

Cl

H 2N HO2C

N Cl

Indications: palliative treatment of multiple myeloma and non-resectable ovarian carcinoma (some breast cancer) Oral or IV, severe bone marrow suppression resulting in infection and bleeding Dosage reduction may be necessary in renal failure as measured by BUN Known to cause chromosome abnormalities

Melphalan - Alkeran

O R N N H

Nitrosoureas
Cl
O N N O

Prototype
H N Cl

Cl

Indications: Palliative treatment for brain tumors, multiple myeloma, Hodgkins and non-Hodgkins lymphomas

Non-vesicant, I.V. or topical (Gliadel wafer) Highly lipid soluble (may cross BBB)
Long delay in bone marrow suppression (6 weeks) do not give more often than every 6 weeks Indications: Brain tumors and Hodgkins disease
H N

Carmustine - BiCNU, Gliadel

Cl

O N N O

Bone marrow toxicity is cumulative - delayed for 6 weeks Capsule: take on empty stomach to avoid N/V, avoid alcohol Highly lipid soluble allows 50% higher CNS levels

Lomustine - CeeNu

Other Alkylating Agents: Aziridines

N N P N S Thiotepa - Thioplex

Indications: Adenocarcinoma of the breast or ovary, control of intracavity effusions, urinary bladder papillary carcinoma, lymphomas IV use only Cell cycle non-specific agent MOA: Alkylates by ethyleneimine radical disrupting DNA Chain scission

Monitor renal and hepatic function - decrease dosage as appropriate

Monitor blood counts for at least three weeks following cessation of therapy - very highly toxic to bone marrow - discontinue if sharp drop in WBCs or platelets

Other Alkylating Agents

CH3SO3
O3SCH3

Indications: DOC for palliative treatment of chronic myelogenous leukemia (CML)

Bifunctional & selective for bone marrow Very well tolerated drug but severe myelosuppression Used for bone marrow ablation prior to bone marrow transplant, cell cycle non-specific agent Discontinue at first sign of bone marrow abnormalities can cause hyperuricemiause allopurinol to avoid (xanthine oxidase inhibitor) Remission rate ~90% after one dose!

Busulfan - Myleran, Busulfex

(CH3)2N N

N N

N(CH3)2

Indications: Palliative treatment of recurrent or persistent ovarian cancer following first line therapy
Oral administration only-calculate dose based on body surface area, cell cycle non-specific agent Metabolism is necessary to activate this drug

N(CH3)2

Altretamine - Hexalen

Conduct routine neurological examines due to neurotox

Conduct blood counts every month

Methylhydrazines
N H H N CH3

H3C

H N CH3 O

Procarbazine HCl - Matulane

Indications: Hodgkins disease MOA: Free radical methylation of DNA: results in cessation of protein, DNA and RNA synthesis Initial treatment should be considered via hospitalization due to hepatic and renal impairment metabolism in liver and kidneys produce cytotoxic metabolites Capsules, warn patients of ethanol-disulfiram like reactions, avoid sympathomimetics such as cold-cough preps and tyramine containing foods due to possibility of hypertensive crisis

Platinum Alkylating Agents

Cl

NH3 Pt NH3

Indications: Carboplatin - Ovarian carcinoma; Cis-Platin testicular, ovarian and bladder cancers of metastatic type MOA: Cell cycle non-specific agent that results in DNA crosslinking Prodrug aquation or hydration necessary to produce active species - this occurs more rapidly with carboplatin than cis-platin different pharmacokinetics and potency Bone marrow suppression is dose related producing infection and anemia, may be cumulative and require transfusions, dosage adjustment a function of renal creatinine clearance and platelet and neutrophil counts DO NOT use aluminum containing administration sets

Cl

Cis-platin -Platinol-AQ
O O NH 3 Pt O NH3 O

Carboplatin - Paraplatin

NH2 Pt NH2

O O

O O

Oxaliplatin - Eloxatin
New for Sept 2002

Side-effects include hepatotoxicity, severe vomiting (less severe with carboplatin), renal damage, ototoxicity (more severe in children), Analyphylaxis (immediate-treat with epinephrine, antihistamines, corticosteroids)

Crosslinking

Binding of Cisplatin to DNA

The Pt atom is green in this cartoon