Class III Alkylating agents "Nitrogen mustards".
Class III Alkylating agent "Nitrogen mustard". Requires hepatic activation. Different side effects that melphalan and chlorambucil: hepatotoxicity, other nitrogen mustard side effects are eliminated.
Class III Alkylating agent. Chloroethylnitrosurea. Good for treating brain tumors due to lipophilicity. Delayed bone marrow suppression.
Class III Alkylating agent. Chloroethylnitrosurea. Has 3 chloroethyl groups for cross-linking of DNA. Good for treating brain tumors due to lipophilicity. Delayed bone marrow suppression.
Alkylating agent. Platinum cross links DNA. Used in testicular, ovarian and head and neck cancer
Alkylating agent. Platinum cross links DNA. Used for colorectal cancer
Alkylating agent. Platinum cross links DNA. Less renal toxicity than cisplatin and oxaliplatin
Alkylating agent. Nonspecific alkylator after hepatic activation. Used for Hodgkin's lymphoma.
Class II "Natural product". Blocks polymerization of microtubules and prevents mitosis. Side effect of peripheral neuropathy due to signal transduction interruption from microtubule inhibition.
"Natural product". Freezes microtubules in polymerized state and prevents mitosis.
"Natural product". Synthetic analogue of paclitaxel.
"Natural product". Inhibits DNA topoisomerase II, prevents DNA replication due to supercoiling. Used for Hodgkin's lymphoma, diffuse histiocytic lymphoma and small cell lung cancer.
"Natural product". Inhibits DNA topoisomerase I, prevents DNA replication due to supercoiling. Used for metastatic colorectal cancer.
"Natural product". Inhibits DNA topoisomerase I, prevents DNA replication due to supercoiling. Used for ovarian and small cell lung cancer.
"Natural product". Intercalates into DNA and prevents replication. Generates free radicals that chemically react with DNA. Inhibits DNA topoisomerase.
"Natural product". After DNA binding domain links up with DNA, Fe-O2 arm swings in, breaks up pyrimidine ring and causes single-stranded breaks.
Antimetabolite. Inhibits dihydrofolate reductase, preventing FH2 -> FH4. This prevents synthesis of dTMP and thus prevents DNA synthesis. Good for use in combination with 5-fluorouracil.
FH4 used for rescue in patients treated with high-dose methotrexate that have their bone marrow nearly wiped out.
Antimetabolite. Irreversibly inhibits thymidylate synthase, preventing conversion of dUMP to dTMP and thus prevents DNA synthesis. Good for use in combination with methotrexate.
Antimetabolite. Inhibits DNA polymerases and prevents elongation of 3' end if incorporated into DNA where cytosine is normally incorporated, causes premature termination.
Antimetabolite. Inhibits DNA polymerases and prevents elongation of 3' end if incorporated into DNA where cytosine is normally incorporated, causes premature termination, like Ara C. Good activity in advanced breast cancer, non-small cell lung cancer, pancreatic carcinoma and ovarian carcinoma.
Antimetabolite. Has a nitrogen on the 5 carbon where methylation typically occurs. Inhibition of methylation = inhibition of gene expression. 3rd nitrogen also makes it easier for the ring to split open and cause single stranded breaks when incorporated into the DNA where cytosine typically goes.
Antimetabolite. Purine analogue that stops purine biosynthesis.
Enzyme. Cleaves asparagine to limit protein synthesis in leukemia cells. Decreased protein synthesis will have adverse affects on the liver and pancreas. Also since the enzyme comes from E. Coli you can have immune reactions against it.
Kinase inhibitor. Inhibitor of c-abl tyrosine kinase. Used to treat CML due to t(9;22) with abl gene translocation.
Kinase inhibitor. Inhibits phosphorylation of HER1 (EGFR) and prevents angiogenesis, proliferation and motility of neoplastic cells. Note that HER1 can mutate and become resistant to Erlotinib.
Kinase inhibitor. Blocks the vulnerable mutant tyrosine kinase (BRAF) in malignant melanoma and colorectal carcinoma, normal cells are insensitive to this drug.
Kinase inhibitor. Blocks the internal kinase that is normally activated by VEGF and prevents angiogenesis.
Antibody. Blocks extra-cellular domain of tyrosine kinase (HER1 EGFR)
Antibody. Blocks extra-cellular domain of tyrosine kinase (HER2 EGFR)
Antibody. Anti-VEGF antibody that prevents tumor angiogenesis.
Antibody. Anti-CD20 monoclonal antibody that promotes complement-mediated lysis of malignant B-cells in non-Hodgkin's lymphoma.
Antibody. Anti-CD33 monoclonal antibody, which hits myeloid cells.
Biological response modifier.
Biological response modifier. Proteosome inhibitor, prevents activation of NF-kB and thus prevents activation of oncogenes. Used in multiple myeloma.
Biological response modifier. Basically vitamin A, used for treatment of promyelocytic leukemia.
If breast cancer is a hormone-dependent cancer, what is prostate cancer?
What is the second most commonly diagnosed cancer in the US?
Lung. Breast is 1st in women and prostate is 1st in men.
What is the cancer with the highest death rate in the US?
What happens in the different phases of the cell cycle shown below?
Class 1 chemotherapeutic drugs
Kills normal cells just as well as it kills neoplastic cells. Has a log dose response
Log dose response
For each increment in dosing, you kill a constant fraction of the remaining cells (always kill 90% of remaining cells with each increase in dose)
Class 2 chemotherapeutic drugs
Kills cells at a specific phase in the cell cycle. Since normal cells are not replicating as quickly, the neoplastic cells are very sensitive to treatment and die off more quickly.
Class 3 chemotherapeutic drugs
Drugs that do not disrupt the cell cycle, but target cancer cells over healthy cells. (Cells that damage DNA, cancer cells replicate so quickly that DNA can't be repaired by S phase and they arrest)
How does the mitotic rate in malignant cells differ from that in their healthy counterparts?
It is about the same
Neoplastic cells with the highest labeling indices
Burkitt's lymphoma. This is easily treatable because the cells run through the cell cycle so rapidly.
Where do cells in a tumor divide most slowly?
Furthest away from nutrients (blood vessels). Eventually cells become necrotic.
Why do people have a better prognosis with breast cancer if it is diagnosed on mammography vs. self examination?
Self examination = 1gm tumor = 30 divisions = neoplastic cells not dividing as rapidly and not as responsive to chemotherapy. Mammogram = earlier detection = more rapidly dividing cells = better response to chemotherapy.
At what point in tumor growth are you worried that cells have mutations that make them resistant to chemotherapy?
Why does nature make it difficult on us when we are trying to treat with chemotherapy?
Tumors can overexpress multi-drug efflux pumps that kicks your chemo out of the cell and makes it ineffective
What may be responsible for treating a tumor with chemotherapy that rids the patient of the cancer, but it continues to relapse?
Tumor cells have stem cells, partially differentiated cells, differentiated cells and totally differentiated cells. If the chemotherapy can't get the stem cells the tumor will keep coming back.
Why do you often need a smattering of chemotherapy drugs in a patient with metastatic cancer?
As the tumor grows and metastasizes it mutates into different clones and you end up treating several different diseases that stemmed from the single neoplastic cell.
What is the mechanism of DNA damage caused by alkylating agents?
Alkylation of the N7 of a purine ring. When alklylated rings are on opposite strands, they cross-link and DNA cannot be repaired.
Do all alkylating agents have to be dichloryl ethyls?
No, you can also have alkane sulfonates
Why use chloroethylnitrosurea over nitrogen mustards?
Chloroethylnitrosurea are the only alkylating agents that are lipid soluble enough to get into the brain. They also have delayed bone marrow suppression.
Why should you offer encouragement to a patient who has lost their hair from chemotherapy?
It means the drug is making it to the hair follicle, which can be a place for the cancer to hide because it is an immunoprotected site.
What drug would you never give intrathecally to a patient?
Vincristine. It inhibits microtubule polymerization and thus inhibits neuronal signal transductions.
What two drugs would you not use in combination that both inhibit mitosis?
Vincristine (blocks polymerization of microtubules) and paclitaxel (freezes microtubules in polymerized state)
What drugs are you likely resistant to if you are resistant to vincristine?
Paclitaxel, etoposide, teniposide, irinotecan, topotecan, daunorubicin, doxorubicin. They are all pumped out by MDR efflux pumps. Note that bleomycin is not a substrate for the pump.
Side effects specific to the anthracyclines (daunorubicin and doxorubicin)
Extremely cardiotoxic because cardiac myocytes cannot remove free radicals as easily as other cells can. Radiation therapy will triple toxicity because it will cause more production of radicals and electrons shooting out.
Conjunctive therapy with anthracyclines
Dexrazoxane: iron chelator that inhibits free radical formation and reduces cardiac damage
What chemotherapy drug would you never use with supplemental oxygen.
Bleomycin. It needs O2 to bind to Fe to work and there is the most O2 in the lungs.
On what side of nucleotide synthesis do you not really need replenishment of FH4?
Purine synthesis. In pyrimidine synthesis, FH4 is consumed in the formation of dTMP and must be replenished.
If a cell has 100 molecules of dihydrofolate reductase, how many dihydrofolate reductases does the cell need to support synthesis of dTMP? How does this affect treatment with methotrexate?
2. The cells can become resistant to methotrexate by amplification of dihydrofolate reductase gene, DHFR, (say 1000 enzymes, when you still only need 2) and methotrexate is no longer effective.
Why can't you just ramp up methotrexate when a person begins synthesizing increased amounts of dihydrofolate reductase?
You'll wipe out the bone marrow and generate toxic metabolites in the liver.
How do you keep yourself from getting into trouble when using 6--mercaptopurine/6-thioguanine as far as side effects go?
Lots of turnover of nucleotides causes build up of uric acid. Treatment with allopurinol to inhibit xanthine oxidase will relieve uric acid levels, but you HAVE TO remember to back off on 6-MP levels otherwise they will accumulate to toxic concentrations.
What enzyme level of activity do you need to know when prescribing 6-MP to a cancer patient?
Thiopurine methyltransferase (TPMT). Some people have low, medium and high levels of enzyme activity. You need to know this for dosing so the patient doesn't get high levels of this cytotoxic drug accumulating.