112 terms

Cancer Chemotherapy

Terminology: carcinoma
epithelial origin
Terminology: sarcoma
connective or muscle origin
Terminology: lymphoma
lymphatic tissue (Hodgkin's: distinctive cell type)
Terminology: leukemia
Hematopoetic origin
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
amount of similarity between cells in a tumor (not all cells in the tumor are the same)
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
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
Oral or IV, Inactive prodrug metabolized in liver by CYP 450 to form active drug distributed in body
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
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\
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)
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