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Terminology: carcinoma

epithelial origin

Terminology: sarcoma

connective or muscle origin

Terminology: lymphoma

lymphatic tissue (Hodgkin's: distinctive cell type)

Terminology: leukemia

Hematopoetic origin
-acute/chronic

Terminology: myelogenous leukemia

abnormal appearing WBC

Terminology: lymphocytic leukemia

high lymphoblast count (young WBC)

Terminology: myeloma

muscle tissue

Terminology: neuroblastoma

neuroendocrine tumor

Terminology: melanoma

skin pigment cells

Generation time

amount of time for a cell to move through the entire cell cycle

Doubling time

amount of time it takes the cells in a tumor to increase by 100%

Growth fraction

percentage of cells actively dividing at any given point in time

Tumor burden

number of cells in tumor

Heterogenicity

amount of similarity between cells in a tumor (not all cells in the tumor are the same)

Differentiation

amount of similarity between tumor cells and the parent tissue (in melanoma, how far from original)

Tumor cells susceptible to anticancer drugs

Only dividing cells (~5% of tumor volume), resting cells in G0 induced into proliferation

Mass of cancer cells for clinical detection

10^9 cells: 1g
30 doublings

Lethal mass of cancer cells

10^12 cells: 1kg
About 40 doublings

Gomperzian growth

Exponential tumor growth until rate decreases due to lack of oxygen and nutrients (central part may be necrotic)

Tumor doubling time

Burkitt's lymphoma: 1 day
Lung cancer: 90 days

Chemotherapy drugs: cytotoxic agents

Alkylating agents, antimetabolites, plant derivatives, cytotoxic antibiotics

Drug chemotherapy: hormones

Suppress natural hormone secretion or antagonize hormone action

Log-kill hypothesis

Given dose of drug kills same percentage of tumor cells with each treatment (rather than same number of tumor cells), surgery can remove large percentage then chemotherapy 90-99% and reapply when regrows until decrease to 0

Complete tumor response

Absence of all tumor for at least one month

Partial tumor response

>50% reduction in measurable tumor for at least one month

Stable disease

<50% reduction or <25% increase in cancer size (not growing too much)

Progression (tumor response)

>25% growth of tumor

Subjective tumor response

Unable to measure tumor response size

Cell cycle-specific drugs

Antimetabolites (S), mitotic inhibitors (M), asparginase (G1 and S), bleomycin (G2), etoposide (G2)
Requires long presence in body to catch cells present in specific stage

Example of schedule-dependent drugs (in M-phase)

Vincristine- causes mitotic arrest, effective only in M-phase on mitotic spindle

Therapeutic index

LD50/ED50

Major chemotherapy toxicities: Bone marrow suppression

Neutropenia: low WBC (G-CSF-filgrastim & GM-SCF-sargramostim)
Thrombocytopenia: low platelet count (Oprelvekin-IL-11, Neumega)
Anemia: low RBC (erythropoietin)

Major chemotherapy toxicities: digestive tract problems

Stomatitis: inflammation of oral mucosa
Diarrhea: impaired nutrient absorption

Major chemotherapy toxicities: nausea and vomiting

Occurs in 17-98% (psychological factors)
Ondansetron (Zofran) and others

What are the major toxicities of cancer drugs?

Bone marrow suppression, stomatitis, diarrhea, nausea and vomiting, alopecia, sterility in males, hyperuricemia, IV local toxicity, carcinogenesis

Inefficiency of anticancer therapy

Multiclonal nature of cancer (cancer stem cells), high mutation rate, cellular adaptation and repair mechanisms

Resistance to anticancer drugs

Decreased drug uptake by cell, reduced drug activation, increased drug activation, stimulation of alternative metabolic pathways, rapid repair of drug induced lesions, reduced affinity to drug target

Resistance to cytotoxic drugs

Increased expression of MDR-1 gene for Pgp (contraindication for cells with large Pgp expression)-performs drug efflux

Resistant drugs from MDR-1

Anthracyclines, vinca alkaloids, and epipodophylootoxins

Multidrug resistant-reversing drugs

Verapamil, quinidine, and cyclosporine (affect Pgp)

Cancers responsive to chemotherapy

Hidgkins lymphoma, ALL, choriocarcinoma, Wlim's tumor (nephroblastoma), testicular and germline cancers, melanomas

Cancers possibly responsive to chemotherapy

Breast, ovarian, endometrial, myeloma, large intestine, esophageal

Cancers unresponsive to chemotherapy

Thyroid, brain, liver, malignant melanoma, pancreatic, cervical

Combination chemotherapy

Different drugs that exert effect through different mechanisms and at different stages of cell cycle

Targeted anticancer therapy: regional drug delivery

Targets blood vessels that enter tissue: intra-arterial (solid tumors), intrathecal (CNS delivery, non-BBB), intracavity (pleural, peritoneal bladder), portal vein (liver), brain implants

Targeted anticancer therapy: targeted treatment

Small molecules or antibodies against surface molecules overexpressed by tumors (increased capillary leaking in tumor cells with high MW compounds), angiogenesis inhibitors, delivery systems

Alkylating agents

Nitrogen mustards: cyclophsphamide
Nitrosoureas: carmustine
Alkyl sulfonates: busulfan
Alkylating-related agents: cisplatin

Alkylating agents mechanism of action

Chemical groups covalently bind cell nucleophiles, form carbonium ions, alkylate DNa mostly at N7 position of guanine, 2 reactive groups bifunctional, DNA intra- and inter-strand x-linking

Usage of alkylating agents

Cell-cycle non-specific, most toxic for rapidly dividing cells, treats both solid and blood malignancies, causes lymphocytopenia, prodrugs metabolized into active drugs within body, toxic-require careful administration

Mechanism of nitrogen mustards

Similar to other alkylating agents, loos of -Cl causes intramolecular cyclization of side chain, reactive ethylene immonium derivative

Cyclophosphamide

Oral or IV, Inactive prodrug metabolized in liver by CYP 450 to form active drug distributed in body

Nitrosoureas

Alkylating agents, x-link DNa and proteins, prodrugs that spontantenously decompose to become active, highly lipophilic, can cross BBB

Platinum compounds

Inserted into DNA structure at minor groove and prevents replication and translation of bound cells, Cl- dissociates for intrastrand crosslink
Active at all stages of cell cycle, esp G1 and S, used in solid tumors

Adverse effects of alkylating agents

Local toxicity at injection site: IV needs to be diluted and slowly infused, dose limiting toxicity- bone marrow depression, nausea and vomiting, alopecia, neurotoxicity, ototoxicity and nephrotoxicity, hemorrhagic cystitis (leakage)

Resistance to alkylating agents

Decreased cell uptake, increased DNA repair, elevated glutathione, induced metallotionein, pathways prevent and neutralize radiocals or ions attack DNA

Antimetabolites

Folic acid analogs: methotrexate
Purine antagonists: 6-mercaptopurine, thioguanine, fludarabine, cladribine
Pyrimidine antagonists: fluorouracil, cytarabine, gemcitabine, capecitabine

Antimetabolites mechanism

Mimic structures of normal metabolites: competitive inhibitors or inappropriate structures
cell cycle specific: S phase
folate antagonists and pyramidine/purine analogs

Bioconversion of folate

Reduced by DHFR, coupled to activity of thymidylate synthase\
folate-->FH2-->FH4

Methotrexate

Uptake through folate transport sys, higher affinity for DHFR than FH2, depletion of dTMP-"thymineless death", orally, IM, IV or intrethecally, doesn't cross BBB

Uses of methotrexate

ALL, meningeal leukemia, choriocarcinoma, osteosarcome, mycosis fungoides, Burkitt's and non-Hodgkin's lymphoma, breast cancer, head and neck, ovary, and bladder
Low dose: psoriasis, rhematoid arthritis, Chron's disease

Methotrexate toxicity

Bone marrow suppression (rescue with leucovorin, folinic acid)
nephrotoxicity (give sodium bicarbonate to reduce loca urine effects)
GI disturbances (mucositis)

Leucovorin

Antidote to methotrexate to rescue bone marrow and GI mucosa
Enhances effect of 5-fluorouracil in colon cancer by inhibiting thymidylate synthase
Doesn't require DHFR for bioconversion

Resistance to methotrexate

Decreased drug transport into cell,
Decreased formation of cytotoxic MTX polyglutamates,
Gene amplification-->Synthesis of increased DHFR levels,
Altered DHFR enzyme, lower methotrexate affinity

Purine antagonist examples

6-mercaptopurine, thioguanine, fludarabine phosphate, cladribine

6 mercaptopurine mechanism

prodrug converted by HGPRT to nucleotide, incorporated into nucleic acids-->nonfunctional RNA and DNA
Inhibits numerous enzymes of purine nucleotide interconversion

Use of 6-mercaptopurine

Acute lymphocytic leukemia (ALL)

Toxicity of 6-mercaptopurine

Immune cell toxicity: myelosuppression, immunosuppression, hepatotoxicity

Resistance to 6-mercaptopurine

Decreased HGPRT (can't convert prodrug to active nucleotide form),
increased cellular alkaline phosphatase (increased dephosphorylation of thiopurines),
increased expression of TMPT (increased metabolism of drug)

Fludarabine phosphate mechanism

Prodrug phosphorylated intracellularly by deoxycytidine kinase to triphosphate form:
Inhibits DNA synthesis and repair (by DNA pol),
Inhibits ribonucleotide reductase,
induces apoptosis

Use of fludarabine phosphate

Non-Hodgin's lymphoma and Chronic lymphocytic leukemia (CLL)

Toxicity of fludarabine phosphate

Myelosuppression, immunosuppression, fever, myalgias, and arthralgias

Cladribine mechanism

High specificity for lymphoid cells
Prodrug phosphorylated by deoxycytidine kinase and incorporated into DNA:
inhibits DNA synth and repair (by DNA pol),
causes DNA strand breaks

Uses of cladribine

Hairy cell leukemia, CLL, non-Hodgkin's lymphoma
Normally administered as a single continuous 7-day infusion

Pyrimidine antagonist examples

5-fluorouracil (5-FU), cytarabine, gemcitabine, capecitabine (5-FU prodrug)

5-fluorouracil mechanism

Prodrug, series of activation steps, several active metabolites
FdUMP inhibits DNA synthesis (thymineless death)
FUTP incorporates into RNA (inhibits of DNA synthesis)

Therapeutic use of 5-Fluorouracil

Treating colorectal cancer and solid tumors, metastatic carcinomas of breast and GI tract, hepatoma, carinomas of ovary, cervix, urinary bladder, prostate, pancreas and oropharyngeal area; enhanced by folic acid coadministration (enhanced inhibition of thymidylate synthase)

Toxicity of 5-fluorouracil

Nausea, mucositis, diarrhea, bone marrow depression, and neurotoxicity

Resistance of 5-fluorouracil

Decreased activity of enzymes necessary to convert 5-FU into active form (FdUMP), increased thymidylate synthase levels, altered thymidylate synthase with lower affinity to 5-FU

Cytarabine (cytosine arabinoside or ara-C)

analogue of 2-deoxycytidine, phosphorylated in vivo to cytosine arabinoside triphosphate

Mechanism of cytarabine (ara-C)

Inhibits DNA pol--> interferes with DNA synthesis and repair, incorporated into RNA and DNA, cell-cycle specific agent, kills cells in S-phase

Use of Cytarabine

Exclusively in hematologic malignancies (ALL, non-Hodgkin's lymphoma), no activity in solid tumors, continuous IV infusion or SC injections every 8hr for 5-10 days

Toxicity of Cytarabine

Bone marrow suppression (producing severe leukopenia, thrombocytopenia and anemia), GI tract disturbances-->stomatitis, nausea/vomiting, cerebellar ataxia, alopecia

Cytarabine resistance

Decreased deoxycytidine kinase (produces ara-CMP), increased cytidine deaminase (converts into inactive metabolites), decreased affinity of DNA polymerase (for araCTP), decreased cellular uptake of ara-C

Types of Plant Alkaloids

Vinca Alkaloids (vinblastine), podophyllotoxins (etoposide), Camptothecins (topotecan), Taxanes (paclitaxel)

Mechanism of vinca alkaloids

Bind to microtubular protein tubulin-->inhibit microtubuli (spindle assemnbly)-->induce mitotic cell arrest at metaphase (cell cycle specific in M-phase), tubulin binding effects: phagocytosis/chemotaxis, axonal transport in neurons

Uses of vinblastine

Hodgkin's disease, non-Hodgkin's lymphomas, breast cancer, germ cell cancer

Toxicity of vinblastine

Nausea, vomiting, bone marrow suppression, alopecia

Use of Vincristine

w/prednisone for remission of ALL, hematologic malignancies (Hodgkin's and nHL, multiple myeloma), pediatric tumors (rhabdomyosarcoma, neuroblastoma, Ewing's sarcoma and Wilm's tumor)

Toxicity of Vincristine

Neurotoxicity (peripheral sensory neuropathy), myelosupression

Podophyllotoxin mechanism

Form drug-DNA-topo II complex, inhibits topo II, induces DNA strand breakage, block cells in late S-G2 phase of cell cycle

Administration of Podophyllotoxins

IV (special formulation-Cremophor) due to low water-solubility, high lipophilicity

Camptothecins mechanism

bind to and stabilize DNA-topo I complex, induce DNA breaks

Use of Camptothecins: topotecan

Advanced ovarian cancer, small cell lung cancer

Use of camptothecins: irinotecan

Metastatic colon and rectal cancer

Toxicity of camptothecins: topotecan

Neutropenia, throbocytopenia, anemia

Toxicity of camptothecins: irinotecan

severe diarrhea, myelosuppression (neutropenia)

Resistance of camptothecins

Transport drugs out of cell, downregulation or mutation of topo I

Taxane mechanism

Enhance tubulin polymerization, stabilize (freeze) microtubuli in polymerizes state, lead to mitotic spindle poison

Use of taxanes

Paclitaxel: advanced ovarian cancer and metastatic breast cancer; docetaxel- advanced breast cancer, non-small cell lung, prostate and gastric cancers

Toxicity to Taxanes

DLT-bone marrow suppression (neutropenia), nausea/vomiting, cumulative neurotoxicity, hypersensitivity reactions (low solubility of paclitaxel and Cremophor vehicle_

Resistance to Taxanes

Increased Pgp expression, tubulin mutations

Cytotoxic antiboiotics

Anthracyclines (doxorubicin), dactinomycin, bleomycin

Anthracycline structure

Microbial origin, high affinity binding to DNA through intercalation-->blockade of DNA and RNA synthesis

Mechanism of anthracyclines

DNA strand scission via effects on Topo II, binding alters membrane fluidity, generation of semiquinone free radical and oxygen radicals

Anthracycline used incombination with:

cyclophsphamide, cisplatin and nitrosoureas

Use of anthracyclines

Carcinomas (breast, endometrial, ovarian, testicular, thyroid, lung), Sarcomas (Ewing's, osteosarcoma, Rhabdomyosarcoma), Hematologic (acute leukemia, multiple myeloma, Hodgkin's disease, nHL)

Toxicity of Anthracyclines

Transient bone marrow suppression, alopecia, irreversible, dose-dependent cardiotoxicity (acute: rhythm disturbances, chronic: congestive cardiomyopathy)

Resistance of anthracyclines

Multidrug resistance

Actinomycin D structure

Polypeptide antibiotic from streptomyces

Actinomycin D mechanism

Intercalates in DNA minor groove between adjacent GC pairs, forms stable dactinomycin-DNA complex, interferes with RNA pol mvmt-decreased transcription, may influence topo II or make free radicals

Actinomycin D use

Wilm's tumor (kidney in children) w/vincristine and cyclophosphmide and surgery and radiotherapy, gestational choriocarcinoma with methotrexate, and metastatic testicular carcinomas with chlorambucil and meethotrexate

Toxicity of Actinomycin D

Bone marrow depression, oral ulcers, skin eruptions and immunosuppression

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