Week 7 - Chapter 102 - Anticancer Drugs I Flashcards
Alkylating Agents
This is on the list of Cytotoxic Anticancer Drugs. An example is Cyclophosphamide - Cell cycle phase non-specific
- It’s Highly reactive compounds
- It’s Mechanism of action is:
- > Alkylation (e.g. tacking on a methyl group) of DNA
- -Monofunctional = One reactive site
- -Bifunctional = Two reactive sites, can crosslink DNA
- > Disrupts DNA replication, transcription
- > Alkylation (e.g. tacking on a methyl group) of DNA
- Cell-cycle phase–nonspecific agents
- Drug resistance is common
- Toxicities - occur in tissues with high growth fraction
- Bone marrow, hair follicles, GI mucosa, germinal epithelium
Antimetabolites
This is on the list of Cytotoxic Anticancer Drugs. An example is Methotrexate (Leucovorin Rescue).
- It’s similar to antimicrobial antimetabolites, block normal metabolism with synthetic mimic molecules
- Folic acid analogs: S-Phase specific & Methotrexate (Leucovorin Rescue)
Antitumor Antibiotics
This is on the list of Cytotoxic Anticancer Drugs. An example is Doxorubicin.
- Used to treat only cancer, not infection
- Prevents separation of complementary DNA strands necessary for transcription, replication – Cell cycle non-specific
- Doxorubicin
- > Vesicant: IV administration, with caution!
- > Toxicities: Typical ones, also delayed cardiotoxicity
- Cytotoxic drugs originally isolated from cultures of Streptomyces
Bifunctional Agents
A type of alkylating agent with two reactive sites able to bind DNA in two places to form cross-links, thereby preventing DNA replication. These bridges may be formed within a single DNA strand or between parallel DNA strands. Also, these agents are more effective than monofunctional agents.
Ex:
-Cyclophosphamide,
-Mechlorethamine,
-Melphalan,
-Nitrosoureas [Carmustine (Bcnu), Lomustine (Ccnu) & Streptozocin]
-Busulfan (One use: chronic myelogenous leukemia)
Platinum-containing drugs are similar to bifunctional agents (Cisplatin, carboplatin, and oxaliplatin)
-Mitomycin
Cell-Cycle Phase Nonspecific Drugs
- The [BLANK] drugs can act during any phase of the cell cycle, including G0. Among the [BLANK] drugs are the alkylating agents and most antitumor antibiotics. Because [BLANK] drugs can injure cells throughout the cell cycle, whereas phase-specific drugs cannot, [BLANK] drugs can increase cell kill when combined with phase-specific drugs. Ex: Bifunctional alkylating agents.
- Note: Although the [BLANK] drugs can cause biochemical lesions at any time during the cell cycle, as a rule these drugs are more toxic to proliferating cells than to cells in G0 because cells in G0 have time to repair damage before its too late & toxicity may not manifest until cells proliferate.
Cell-Cycle Phase Specific Drugs
[BLANK] drugs are toxic only to cells that are passing through a particular phase of the cell cycle. Because the dosing schedule is so critical to therapeutic response, [BLANK] drugs are also known as schedule-dependent drugs. [BLANK] are often administered by prolonged infusion.
Ex: Vincristine, for example, acts by causing mitotic arrest, and hence is effective only during M phase. Other agents act by disrupting DNA synthesis, and hence are effective only during S phase. Because of their phase specificity, these drugs are toxic only to cells that are active participants in the cell cycle; cells that are “resting” in G0 will not be harmed. Obviously, if these drugs are to be effective, they must be present as neoplastic cells cycle through the specific phase in which they act. Accordingly, these drugs must be present for an extended time. Alternatively, they can be given in multiple doses at short intervals over an extended time.
Hypomethylating Agents
A new class of anticancer drugs: the [BLANK] agents. This anticancer drug becomes incorporated into DNA and then inhibits DNA methyltransferase, an enzyme that puts methyl groups onto DNA components. The resulting DNA is believed to induce apoptosis and restore normal function to genes critical to cell differentiation and proliferation. In vitro, drug concentrations that cause maximal inhibition of DNA methylation do not cause significant inhibition of DNA synthesis.
Examples of these drugs are Azacitidine [Vidaza] & Decitabine [Dacogen]. Azacitidine has one indication: myelodysplastic syndrome, a bone marrow disorder characterized by reduced blood cell counts and the potential to progress to acute myelogenous leukemia. Toxicities include myelosuppression, nausea and vomiting, and CNS depression. Like azacitidine, decitabine is used only for myelodysplastic syndrome. Toxicities include myelosuppression, nausea and vomiting, and a flu-like syndrome.
Leucovorin Rescue
A technique known as [BLANK] rescue can be employed to enhance the effects of methotrexate. Some neoplastic cells are unresponsive to methotrexate because they lack the transport system required for active uptake of the drug. By giving massive doses of methotrexate, we can force the drug into these cells by passive diffusion. However, because this process also exposes normal cells to extremely high concentrations of methotrexate, normal cells are also at risk. To save them, [BLANK] (citrovorum factor, folinic acid) is given. [BLANK] bypasses the metabolic block caused by methotrexate, thereby permitting normal cells to synthesize thymidylate and other compounds. Malignant cells are not saved to the same extent because [BLANK] uptake requires the same transport system employed for methotrexate uptake, a transport system these cells lack. It should be noted that [BLANK] rescue is potentially dangerous: Failure to administer leucovorin in the right dose at the right time can be fatal.
Mitotic Inhibitors
[Blank} inhibitors are drugs that act during M phase to prevent cell division. There are two major groups of these drugs—vinca alkaloids and taxanes—as well as three other drugs that belong to neither group.
Monofunctional Agents
Alkylating agents with only one reactive site lack the ability to form cross-links, but can still bind to a single guanine in DNA. Less affective than Bifunctional agents.
Topoisomerase Inhibitors
Topoisomerases are nuclear enzymes that alter the shape (topology) of supercoiled DNA. Without the actions of topoisomerases, the double helix would be too tangled to permit DNA replication, RNA synthesis, or DNA repair. How do topoisomerases alter DNA configuration? They make a cut in the DNA strand—which permits the strand to relax in the vicinity of the cut—and then later they reseal the cut. There are two types of topoisomerase, known as topoisomerase I and topoisomerase II. Topoisomerase I makes single-strand cuts, and topoisomerase II makes double-strand cuts. Of the four topoisomerase inhibitors in current use, two—topotecan and irinotecan—inhibit topoisomerase I, and the other two—etoposide and teniposide—inhibit topoisomerase II. The actions of these drugs are partly like those of the antitumor antibiotics discussed above, which inhibit topoisomerase II and intercalate DNA.
Cyclophosphamide
[BLANK}, formerly available as Cytoxan and Neosar, is a bifunctional alkylating agent active against a broad spectrum of neoplastic diseases. Indications include Hodgkin’s disease, non-Hodgkin’s lymphomas, multiple myeloma, and solid tumors of the head, neck, ovary, and breast. Of all the alkylating agents, [BLANK] is employed most widely.
[BLANK] is a prodrug that undergoes conversion to its active form in the liver. Because activation is required, onset of effects is delayed. [BLANK] is not a vesicant, and hence can be administered PO as well as IV. Oral doses should be administered with food.
Methotrexate
[BLANK] (Rheumatrex, Trexall) inhibits dihydrofolate reductase, the enzyme that converts dihydrofolic acid (FH2) into tetrahydrofolic acid (FH4). Since production of FH4 is a necessary step in the activation of folic acid, and since activated folic acid is required for biosynthesis of essential cellular constituents (DNA, RNA, proteins), inhibition of FH4 production has multiple effects on the cell. Of all the processes that are suppressed by reduced FH4 availability, biosynthesis of thymidylate appears most critical. Why? Because, in the absence of thymidylate, cells are unable to make DNA. Because cell kill results primarily from disrupting DNA synthesis, [BLANK] is considered S-phase specific. Please note, however, that in addition to its S-phase effect, [BLANK] has another beneficial action: The fall in thymidine levels caused by [BLANK] is a potent signal for inducing apoptosis (programmed cell death).
Doxorubicin
[BLANK] is a type of Anthracycline. It is active against a broad spectrum of neoplastic diseases. Unfortunately, cardiotoxicity limits its utility. [BLANK] is available in two formulations: conventional [Adriamycin] and liposomal [Doxil, Caelyx image]. The conventional preparation is discussed here. The liposomal preparation is discussed immediately below.
Mechanism of Action.
[BLANK] is a planar (flat) molecule that kills cells by two related mechanisms: intercalation with DNA and inhibition of topoisomerase II. We can understand intercalation by envisioning the stacked base pairs of DNA as having a structure like that of a stack of coins. Having a coin-like shape itself, doxorubicin is able to slip between base pairs of DNA, after which it becomes bound to DNA. This process (intercalation) distorts DNA structure. As a result, DNA polymerase and RNA polymerase are unable to use DNA as a template, and hence synthesis of DNA and RNA is inhibited.
While bound to DNA, [BLANK] forms a complex with topoisomerase II, an enzyme that cleaves and then repairs DNA strands. [BLANK] allows topoisomerase II to cleave DNA, but prevents subsequent DNA repair. In the absence of DNA repair, apoptosis results. Topoisomerase is discussed further below, under Topoisomerase Inhibitors. [BLANK] is cell-cycle phase nonspecific.
Vincristine
[BLANK] is one of two Vina Alkaloids.
Mechanism of Action:
[BLANK] (conventional) [Oncovin, Vincasar PFS] and [BLANK] (liposomal) [Marqibo] block mitosis during metaphase, and thus are M-phase specific. [BLANK] blocks mitosis by disrupting the assembly of microtubules, the filaments that move chromosomes during cell division. To block microtubule assembly, [BLANK] binds with tubulin, the major component of microtubules. In the absence of microtubules, cell division stops at metaphase. Metaphase block is a potent signal for apoptosis (programmed cell death).
Therapeutic Uses:
[BLANK] is bone marrow sparing. Accordingly, the drug is ideal for combination chemotherapy. Indications for conventional [BLANK] include Hodgkin’s and non-Hodgkin’s lymphomas, acute lymphocytic leukemia, Wilms’ tumor, rhabdomyosarcoma, Kaposi’s sarcoma, breast cancer, and bladder cancer. Liposomal vincristine is indicated for Philadelphia chromosome–negative acute lymphoblastic leukemia.
Toxicity:
[BLANK] is toxic to peripheral nerves, but does little damage to bone marrow.
