Chemotherapy Flashcards
Non phase specific agents. Cell-cycle nonspecific agents
Chemotherapy can kill a cell during any phase of the cell cycle,including the resting phase =>Glucocorticoids, antitumoral antibiotics (except bleomycin)
These medicines work best when given in a bolus dose=> a large dose, given over a short period of time. (e.g the dose may be given once over 20 minutes.)
The cells don’t necessarily die right away. A cell may have to go through several cycles before it dies.
Repeat doses of chemotherapy may be given to continue to kill cancer cells.
Non phase specific agents. Cell-cycle specific agents, but non phase specific
Effective at any parts of the cell cycle (not in resting cells) – alkylating drugs
These medicines are often given more than one time. This gives the chemotherapy the best chance to kill as many cells as possible.
They may be given in “divided doses” or given multiple times. For example, once a day for 5 days, or every 3 hours for 4 doses.
They can also be given as a nonstop infusion. This is an infusion that runs for several hours or more. Some chemotherapy infusions are given over several days.
Dose specific effect
Phase specific agents. Cell-cycle specific agents
Chemotherapy medicines kill cancer cells only during a certain phase. They are also not able to work in the resting phase. Ceiling effect – efficacy is not correlating with the dose
Alkalyting agents
Nitrogen mustards: • Cyclophosphamide — the most widely used alkylating agent of modern times. • Chlormethine also known as mechlorethamine or mustine (HN2) — the first alkylating agent to receive regulatory approval. • Uramustine or uracil mustard • Melphalan • Chlorambucil • Ifosfamide • Bendamustine
They stop tumor growth by crosslinking guanine nucleobases in DNA double-helix strands, directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. These drugs act nonspecifically.
Nitrogen mustards
Cyclophosphamide 1956
Prodrug, rich in phosphate 50 mg/m2 in 3 weeks po, 250 mg/m2, v. 150 mg/m2 (VAC) 3 weekly
Toxicity:
- BM (but increased RNC life span, do not act on megakaryocytes), sterile heorrhagic cystitis (antidote: mesna /Uromitexan/), alopecia
Chlorambucil 1952
Attack mature lymphocytes, too. Used in CLL 0.2 mg/kg – 0.1 mg/kg, 2 - 8 mg/m2 po
Melphalan
Decrease plasma cell counts. Used myeloma. 0.1 mg/kg, 1.5 mg/m2 po
Lomustine, CCNU
Lipofilic, penetrate through BBB Brain neopl., multiple myeloma, Hodgkin’s d., adenocarcinoma, hepatoma, chronic leukemias, lymphoma, MGT, ovarian gl. tumours, hist. sarc. No cross reaction with other alkalytic agents No prodrugs. Streptozotocin – contains glucose, used in insulinoma
Toxicity:
- vomiting, myelosuppression, hepatic damage
Sexual hormones and their antagonists
Tamoxifen
use for MGT: 1977 . Tamoxifen is a prodrug, w/ relatively little affinity for its target protein, the estrogen receptor (ER).
- metabolized in the liver by the cytochrome P450 isoform CYP2D6 + CYP3A4 into active metabolites such as 4-hydroxytamoxifen (4-OHT) (afimoxifene) and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have
30–100x more affinity to ER than tamoxifen. These active metabolites compete with estrogen in the body for binding to the ER.
In breast tissue, 4-OHT acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited
Other cytotoxic drugs
Hormons, hormonantagonists Corticosteroids
Prednisolon in lymphoma Cytoplasmic receptorial effect DNA-synth. inh. Toxicity: ulcerative, delayed wound healing
Mitotane (o.p’DDD)
Adrenal cortex zona fasciculata and reticularis destruction, Cushing’s d.
Hydroxyurea
Mechanism of action
-Ribonukleoside-difosphate-reductase inh.
Effect:
-DNA-synth inh. (S-phase)
Application:
-myeloproliferative disease (i.e. CGL, polycythaemia, thrombocytosis, melanoma, hypereosinophilic syndrome). With radiation therapy dog: 50 to 80 mg/kg po 3 daily cat: 25 mg/kg po 3x weekly
Toxicity
- BM.
L-Asparaginase
Mechanism of action
-ALL (acute lymphoblastic leukemia) cells and some other suspected tumor cells are unable to synthesize the non-essential aa asparagine, while normal cells can make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine.
Asparaginase, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death.
Result:
-Difference between tumour and normal cells
Application:
-lymphoma. 10,000 - 12,000 u/m2 im weekly
Toxicity
-anaphylaxic, im, for cats: sq
Antibiotics
Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis
Doxorubicin- Lymphoma, sarcoma, carcinoma.
Toxicity:
-cardiotoxic (myocardium Cametabolism ), in cats nephrotoxic, hypersensitivity, alopecic, local irritation (epirubicin less toxic). /with infusion/ 30 mg/m2 v. 15 mg/m2 (VAC protocol) iv. 3 weekly
Beomycin
Inoperabile SCC - electroporation. 10 units/m2 iv, sc for 3 - 9 days, then weekly
Toxicity:
-GI-tract, pulm. fibr., hyperpigmentation
Mitoxantron Instead of doxo, lymphoma, v. TCC 5.5 mg/m2 IV (dog); 6.5 mg/m2 IV (cat) every 3 weeks Toxicity: -BM, colitis
Actinomycin /Dactinomycin/ „rescue” in lymphoma, carc.: carcinoma (perian., pm, TCC)
0.7 – 1.1 mg/m2 iv 2-3 weekly
Toxicity: gastroenteritis
Camptothecis
Topotecan Ovarial and pulmonary tumours (hum.)
Toxicity: alopecia, vomiting, anemia
Hycamtin
Taxans
Paccal Vet 150 mg/m2 every 3 weeks
Paclitaxel (PTX), used to treat a number of cancers including :ovarian cancer, breast cancer, lung cancer, Kaposi sarcoma, cervical cancer, and pancreatic cancer. Given IV. There is also an albumin-bound formulation
Given : IV ( into urinary bladder with porcine gel.?)
SEs: hair loss, bone marrow suppression, numbness, allergic reactions, muscle pains, and diarrhea, heart problems, increased risk of infection, and lung inflammation
works by interference with the normal function of microtubules during cell division
Podophyllotoxins
Podophyllotoxin possesses a large number of medical applications and can be used as a cathartic, purgative, antiviral agent (HPV1), vesicant, and antihelminthic.
Additionally, podophyllotoxin and its derivatives are precursors for anti-tumor agents such as etoposide and tenoposide.
Etoposide
HPV genital warts, lung, testicule neopl., lymphoma, leukemia, sarcoma.
Toxicity:
-vomiting, diarrhoea, myeloszuppression, AML??
Tenoposide
Acute lymphoid leukaemia (children)
Toxicity:
-BM. 50 mg/m2 po, 10 mg/ml dilution
Vinca alkaloids
Vincristine
Haemopoitetic tumours, sarcomas TVT (transmissible venereal tumours, canine)!!. Stimulate platelet outflow from megakaryocytes. Toxicity: Local irrittion, peripheric neuropathy.
0.7 mg/m2 iv weekly
Vinblastin
Resistant lymphomas, MCT Toxicity: BM, local irrit. 2 mg/m2 iv. weekly
Vinorelbine
Non small cell pulm. carc., metastatic MGT, rhabdomyosarcoma Toxicity: Vomit,inappetance, local irritation 10-15 mg/m2 iv weekly 1x
Antimetabolites
Metothrexate
Folate antagonist, a dihidrofolate reductase inh.,, adenin-, guanin synth. inh..
Toxicity:
BM, ulcerative 2.5 mg/m2 po daily; és 20 mg/m2 iv weekly
Cytosin-arabinoside
2’dezoxicitidin v. pirimidin analogue, repair-inh., increase of cellular differentiation, used in AML 300 mg/m2/day sc for 2 days, v. 50 mg/m2 sc 2x every 3 weeks for 4 months for GME
5-fluorouracil
Uracil-analogue, (F-, instead H-atom), adenocarcinoma. Toxicity:
in cats neuropathy 5-Fluoruracil (5-FU®): 150 mg/m2 weekly 1x
Thioguanin
Guanin-analogue, Lymphoma, leukaemia
Toxicity:
BM 50 mg/m2 po. 1-2 dily 1x
