9: Cancer Lecture II Flashcards
The log-kill hypothesis (first order kinetics) proposes a model for the effect of cytotoxic chemotherapy on tumor size. It states that a given dose of chemotherapy drug kills the same ______ of tumor cells regardless of the size of the tumor.
Furthermore, cell viability decreases with ______ drug concentration & different drugs have different effects on cell viability.
The log-kill hypothesis (first order kinetics) proposes a model for the effect of cytotoxic chemotherapy on tumor size. It states that a given dose of chemotherapy drug kills the same fraction of tumor cells regardless of the size of the tumor.
Furthermore, cell viability decreases with increased drug concentration & different drugs have different effects on cell viability.
Limitations of chemotherapy:
drug resistance: most tumors acquire drug resistance after ______ administration of the drug.
toxicity: Chemotherapeutic agents aimed at killing cancer cells also affect normal cells undergoing ______ proliferation (e.,g., Bone Marrow, GI mucosa, hair follicles).
Limitations of chemotherapy:
drug resistance: most tumors acquire drug resistance after prolonged administration of the drug.
toxicity: Chemotherapeutic agents aimed at killing cancer cells also affect normal cells undergoing rapid proliferation (e.,g., Bone Marrow, GI mucosa, hair follicles).
Based on their actions on cell cycle, anti-cancer drugs are divided into two classes:
Cell cycle-specific (CCS) drugs (e.g. antimetabolites, vinca alkaloids) are effective when a ______ proportion of tumor cells are proliferating (i.e. high growth fraction tumors), such as hematologic malignancies.
Cell cycle-nonspecific (CCNS) drugs (e.g. alkylating agents) kill both ______ and and ______ tumor cells & are effective against both ______ growth fraction tumors like solid tumors as well as ______ growth fraction tumors.
*Growth fraction = the proportion of cells in a tumor that are actively proliferating
Based on their actions on cell cycle, anti-cancer drugs are divided into two classes:
Cell cycle-specific (CCS) drugs (e.g. antimetabolites, vinca alkaloids) are effective when a large proportion of tumor cells are proliferating (i.e. high growth fraction tumors), such as hematologic malignancies.
Cell cycle-nonspecific (CCNS) drugs (e.g. alkylating agents) kill both cycling and and noncycling tumor cells & are effective against both low growth fraction tumors like solid tumors as well as high growth fraction tumors.
*Growth fraction = the proportion of cells in a tumor that are actively proliferating
Alkylating agents transfer an alkyl group to DNA & promote ______ of DNA strands resulting in DNA damage. They are cell cycle ______ agents, hence they act on ______ .
Alkylating agents transfer an alkyl group to DNA & promote cross-linking of DNA strands resulting in DNA damage. They are cell cycle non-specific agents, hence they act on both proliferating and resting cells.
Toxicities of ______ Agents:
Dose-related bone marrow suppression (neutropenia, thrombocytopenia, anemia). Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.
Mucosal toxicity (oral mucosal and GI ulceration)
Nausea and vomiting
Toxic effects on male and female reproductive system
Highly carcinogenic; increased risk of secondary leukemia
Toxicities of Alkylating Agents:
Dose-related bone marrow suppression (neutropenia, thrombocytopenia, anemia). Myelosuppression is a condition in which bone marrow activity is decreased, resulting in fewer red blood cells, white blood cells, and platelets.
Mucosal toxicity (oral mucosal and GI ulceration)
Nausea and vomiting
Toxic effects on male and female reproductive system
Highly carcinogenic; increased risk of secondary leukemia
Specific Alkylating Agents–Nitrogen Mustards:
Mechlorethamine: ______ reactive, first clinically used nitrogen mustard, used in combination chemotherapy regimen MOPP.
Specific Alkylating Agents–Nitrogen Mustards:
Mechlorethamine: most reactive, first clinically used nitrogen mustard, used in combination chemotherapy regimen MOPP.
Specific Alkylating Agents–Nitrogen Mustards:
Cyclophosphamide/ Ifosfamide:
Very broad clinical spectrum, component of many combination regimens. Used for treatment of non-Hodgkin’s lymphoma, breast, lung, and ovarian cancers.
Toxicities: nausea, vomiting, myelosuppression, ** ______ (due to accumulation of toxic metabolite acrolein). administration of ______ minimizes ______.
______ is an inflammation of the bladder that leads to pain and hematuria (blood in the urine).
Cyclophosphamide/Ifosfamide mechanism of action: pro-drug so must be converted to active metabolites by liver cytochrome P450.
If starred ** means very testable.
Specific Alkylating Agents–Nitrogen Mustards:
Cyclophosphamide/ Ifosfamide:
Very broad clinical spectrum, component of many combination regimens. Used for treatment of non-Hodgkin’s lymphoma, breast, lung, and ovarian cancers.
Toxicities: nausea, vomiting, myelosuppression, **Hemorrhagic cystitis (due to accumulation of toxic metabolite acrolein). administration of MESNA (2-mercaptoethane sulfonate) minimizes Hemorrhagic cystitis.
Hemorrhagic cystitis is an inflammation of the bladder that leads to pain and hematuria (blood in the urine).
Cyclophosphamide/Ifosfamide mechanism of action: pro-drug so must be converted to active metabolites by liver cytochrome P450.
If starred ** means very testable.
Specific Alkylating Agents–Nitrosoureas:
Include Carmustine & Lomustine. Carmustine and lomustine are highly ______ (so crosses blood brain barrier); used for treatment of meningeal leukemias and brain tumors.
Toxicity: Severe nausea and vomiting, Profound myelosuppression, ______ toxicity, ______ fibrosis.
Specific Alkylating Agents–Nitrosoureas:
Include Carmustine & Lomustine. Carmustine and lomustine are highly lipophilic (so crosses blood brain barrier); used for treatment of meningeal leukemias and brain tumors.
Toxicity: Severe nausea and vomiting, Profound myelosuppression, Renal toxicity, Pulmonary fibrosis.
Specific Alkylating Agents–Triazenes:
Include Dacarbazine & Temozolomide they are pro-drugs; monoalkylators.
Therapeutic Uses: Dacarbazine is a component of ABVD regimen used for treatment of ______ disease. Temozolomide has shown activity against malignant glioma.
Toxicity: Nausea and vomiting, Myelosuppression, Flu-like symptoms.
Specific Alkylating Agents–Triazenes:
Include Dacarbazine & Temozolomide they are pro-drugs; monoalkylators.
Therapeutic Uses: Dacarbazine is a component of ABVD regimen used for treatment of Hodgkin’s disease. Temozolomide has shown activity against malignant glioma.
Toxicity: Nausea and vomiting, Myelosuppression, Flu-like symptoms.
Specific Alkylating Agents–Platinum Analogs:
Include ______, Carboplatin, Oxaliplatin.
They are ______** platinum derivatives; covalently bind to nucleophilic sites (e.g., N7 of guanine) on DNA; form intrastrand and interstrand cross-links.
Specific Alkylating Agents–Platinum Analogs:
Include Cisplatin, Carboplatin, Oxaliplatin.
They are inorganic** platinum derivatives; covalently bind to nucleophilic sites (e.g., N7 of guanine) on DNA; form intrastrand and interstrand cross-links.
Therapeutic Uses:
Cisplatin** has efficacy against a ______ range of neoplasms; used for treatment of testicular, ovarian, cervical and bladder cancers.
Toxicity:
Cisplatin: ______** (renal tubular damage and necrosis); ______** (hearing loss); peripheral ______**; nausea and vomiting; myelosuppression.
Therapeutic Uses:
Cisplatin** has efficacy against a wide range of neoplasms; used for treatment of testicular, ovarian, cervical and bladder cancers.
Toxicity:
Cisplatin: Nephrotoxicity** (renal tubular damage and necrosis); ototoxicity** (hearing loss); peripheral neuropathy**; nausea and vomiting; myelosuppression.
KNOW SPECIFIC TOXICITIES OF CISPLATIN.
Therapeutic Uses:
Carboplatin is approved for ______ cancer
Oxaliplatin is used in combo w/ ______ for gastric and colorectal cancer
Toxicity:
Carboplatin: less toxic and less reactive; thrombocytopenia is dose-limiting.
Oxaliplatin: unique toxicity- cold-induced acute peripheral neuropathy
Therapeutic Uses:
Carboplatin is approved for ovarian cancer
Oxaliplatin is used in combo w/ 5-FU for gastric and colorectal cancer
Toxicity:
Carboplatin: less toxic and less reactive; thrombocytopenia is dose-limiting.
Oxaliplatin: unique toxicity- cold-induced acute peripheral neuropathy
______ are structural analogs of endogenous folates, purines or pyrimidines. Inhibit enzymes required for ______ synthesis or compete with endogenous nucleotides in DNA or RNA synthesis. Act specifically in the DNA ______ phase of the cell cycle; thus considered as cell cycle specific (CCS) drugs.
Antimetabolites are structural analogs of endogenous folates, purines or pyrimidines. Inhibit enzymes required for neucleotide synthesis or compete with endogenous nucleotides in DNA or RNA synthesis. Act specifically in the DNA synthesis (S) phase of the cell cycle; thus considered as cell cycle specific (CCS) drugs.
Specific Antimetabolites–Folate Analogs: Methotrexate
Methotrexate inhibits the enzyme ______. Dihydrofolate reductase is the enzyme that is required for the synthesis of purines.
most widely used antimetabolite in cancer chemotherapy
produced first striking remissions of leukemia (1948)
produced first cure of a solid tumor (choriocarcinoma, 1963)
Specific Antimetabolites–Folate Analogs: Methotrexate
Methotrexate inhibits the enzyme dihydrofolate reductase (DHFR). Dihydrofolate reductase is the enzyme that is required for the synthesis of purines.
most widely used antimetabolite in cancer chemotherapy
produced first striking remissions of leukemia (1948)
produced first cure of a solid tumor (choriocarcinoma, 1963)
Specific Antimetabolites–Folate Analogs: Methotrexate
Therapeutic Uses:
effective in treating childhood ALL, choriocarcinoma, osteosarcoma, breast cancer, head and neck cancer.
usually given orally; administered intrathecally for meningeal leukemia
Toxicity
Bone marrow toxicity (myelosuppression)
GI toxicity (oral ulceration, stomatitis)
______ toxicity** (MTX can crystallize in the urine and cause renal damage)
______** (long-term use of MTX may lead to fibrosis or cirrhosis)
Leucovorin rescue - Leucovorin (N-5 formyltetrahydrofolate) is administered to the patient several hours after an otherwise lethal dose of methotrexate. The rationale for this technique is that the malignant cells are killed selectively, while the normal cells are “rescued” by the folinic acid. One hypothesis is that tumor cells cannot uptake folinic acid (Leucovorin) whereas normal cells can uptake folinic acid and bypass the requirement of DHFR.
Specific Antimetabolites–Folate Analogs: Methotrexate
Therapeutic Uses:
effective in treating childhood ALL, choriocarcinoma, osteosarcoma, breast cancer, head and neck cancer.
usually given orally; administered intrathecally for meningeal leukemia
Toxicity
Bone marrow toxicity (myelosuppression)
GI toxicity (oral ulceration, stomatitis)
Renal toxicity** (MTX can crystallize in the urine and cause renal damage)
Hepatotoxicity** (long-term use of MTX may lead to fibrosis or cirrhosis)
Leucovorin rescue - Leucovorin (N-5 formyltetrahydrofolate) is administered to the patient several hours after an otherwise lethal dose of methotrexate. The rationale for this technique is that the malignant cells are killed selectively, while the normal cells are “rescued” by the folinic acid. One hypothesis is that tumor cells cannot uptake folinic acid (Leucovorin) whereas normal cells can uptake folinic acid and bypass the requirement of DHFR.
Specific Antimetabolites–Pyrimidine Analogs: 5-Fluorouracil (5-FU)
A pro-drug; enzymatically converted into active metabolite 5-FdUMP. 5-Fluorouracil inhibits ______ which inhibits dTMP synthesis, dTMP is a building block of DNA.
Therapeutic Uses
Must be given IV due to rapid metabolic degradation in the gut and liver. Used as a component of combo regimens for treatment of breast, colorectal, gastric, head and neck, cervical and pancreatic cancers. Used topically for basal cell carcinomas.
Toxicity
Anorexia and nauseam Mucosal ulcerations, stomatitis and diarrhea, Thrombocytopenia and anemia, Hand-foot syndrome- erythema, sensitivity to the palms and soles, Cardiac toxicity- acute chest pain.
Specific Antimetabolites–Pyrimidine Analogs: 5-Fluorouracil (5-FU)
A pro-drug; enzymatically converted into active metabolite 5-FdUMP. 5-Fluorouracil inhibits thymidylate synthase which inhibits dTMP synthesis, dTMP is a building block of DNA.
Therapeutic Uses
Must be given IV due to rapid metabolic degradation in the gut and liver. Used as a component of combo regimens for treatment of breast, colorectal, gastric, head and neck, cervical and pancreatic cancers. Used topically for basal cell carcinomas.
Toxicity
Anorexia and nauseam Mucosal ulcerations, stomatitis and diarrhea, Thrombocytopenia and anemia, Hand-foot syndrome- erythema, sensitivity to the palms and soles, Cardiac toxicity- acute chest pain.
Specific Antimetabolites–Pyrimidine Analogs: Cytarabine (Ara-C)
Cytarabine (Ara-C) is an analog of 2’-deoxycytidine (natural ribose is replaced by D-arabinose). Converted to Ara-CMP by deoxycytidine kinase. Ara-CMP is subsequently converted to Ara-CTP, which competes with dCTP for incorporation into ______ by DNA polymerase (dCTP is one of the building blocks of DNA synthesis). When incorporated into DNA, Ara-CTP inhibits DNA synthesis.
Therapeutic Uses
Most effective for treatment of AML, also useful for ALL and blast phase CML.
Toxicity
Severe myelosuppression, GI tract toxicity (ulceration, stomatitis, diarrhea)
Specific Antimetabolites–Pyrimidine Analogs: Cytarabine (Ara-C)
Cytarabine (Ara-C) is an analog of 2’-deoxycytidine (natural ribose is replaced by D-arabinose). Converted to Ara-CMP by deoxycytidine kinase. Ara-CMP is subsequently converted to Ara-CTP, which competes with dCTP for incorporation into DNA by DNA polymerase (dCTP is one of the building blocks of DNA synthesis). When incorporated into DNA, Ara-CTP inhibits DNA synthesis.
Therapeutic Uses
Most effective for treatment of AML, also useful for ALL and blast phase CML.
Toxicity
Severe myelosuppression, GI tract toxicity (ulceration, stomatitis, diarrhea)
Specific Antimetabolites–Pyrimidine Analogs: Gemcitabine
a difluoro analog of deoxycytidine (dFdC)
converted to active di- and tri-phosphate metabolites (dFdCDP, dFdCTP)
dFdCDP inhibits ______, resulting in the depletion of deoxyribonucleotides necessary for DNA synthesis. Ribonucleotide reductase makes deoxyribonucleotides.
dFdCTP competes with dCTP for incorporation into DNA and leads to termination of DNA synthesis
more effective in treating solid tumors than cytarabine
Therapeutic Uses
used as a first-line treatment for pancreatic cancer & also effective against non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer
Specific Antimetabolites–Pyrimidine Analogs: Gemcitabine
a difluoro analog of deoxycytidine (dFdC)
converted to active di- and tri-phosphate metabolites (dFdCDP, dFdCTP)
dFdCDP inhibits ribonucleotide reductase, resulting in the depletion of deoxyribonucleotides necessary for DNA synthesis. Ribonucleotide reductase makes deoxyribonucleotides.
dFdCTP competes with dCTP for incorporation into DNA and leads to termination of DNA synthesis
more effective in treating solid tumors than cytarabine
Therapeutic Uses
used as a first-line treatment for pancreatic cancer & also effective against non-small cell lung cancer, ovarian, bladder, esophageal, and head and neck cancer
Specific Antimetabolites–Purine Analogs: 6-Mercaptopurine (6-MP)
6-Mercaptopurine (6-MP) is a pro-drug; requires enzymatic conversion to ribonucleotide by ______. A pro drug means that it needs conversion to a active metabolite to work.
Therapeutic Uses
used primarily to maintain remission in patients with ALL
Toxicity is bone marrow suppression, hepatotoxicity in prolonged use of 6-MP
Mechanism of Resistance decreased expression of HGPRT, decreased drug transport
**6-Mercaptopurine (6-MP) interaction with ______, which is used to treat hyperuricemia. ______ inhibits xanthine oxidase and thereby increases plasma MP levels.
It is important to decrease the dose of 6-MP in patients receiving ______ to avoid accumulation of the drug and exacerbation of toxicities.
Specific Antimetabolites–Purine Analogs: 6-Mercaptopurine (6-MP)
6-Mercaptopurine (6-MP) is a pro-drug; requires enzymatic conversion to ribonucleotide by HGPRT. A pro drug means that it needs conversion to a active metabolite to work.
Therapeutic Uses
used primarily to maintain remission in patients with ALL
Toxicity is bone marrow suppression, hepatotoxicity in prolonged use of 6-MP
Mechanism of Resistance decreased expression of HGPRT, decreased drug transport
**6-Mercaptopurine (6-MP) interaction with allopurinol, which is used to treat hyperuricemia. Allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels.
It is important to decrease the dose of 6-MP in patients receiving allopurinol to avoid accumulation of the drug and exacerbation of toxicities.
Note: HGPRTase functions primarily to salvage purines from degraded DNA to reintroduce into purine synthetic pathways.
