cancer 2 Flashcards
combination chemotherapy is more
effective than single-drug treatment in most cancers
what are the 5 examples of combination regimens?
- ABVD
- CHOP
- MOPP
- CMF
- FEC
ABVD
doxyrubicin (adriamycin), bleomycin, vinblastine, decarbazine
CHOP
cyclophosphamide, hydroxydoxorubicin, vincristine, prednisone
CMF
cyclophosphamide, methotrexate, 5-Fu
FEC
5-FU, epirubicin, cyclophosphamide
based on the mechanism of action, name the 7 classes of anticancer
- alkylating agents
- antimetabolites
- DNA intercalating agents
- microtubule inhibitors
- topoisomerase inhibitors
- hormones and their antagonist
- miscellaneous agents
What are alkylating agents?
a group of compounds that have the ability to transfer an alkyl group to DNA
alkylations promote
cross-linking of DNA strands resulting in DNA damage
sulfur mustards were used
as chemical warfare agents in WW1
what are some major classes of alkylating agents?
- cyclophosphamide
- ifosfamide
- carbustine
what is the mechanism of action of the alkylating agents?
produce strong electrophiles through the formation of carbonium or ethyleneimonium ion intermediates, which form covalent linkages by alkylation of nucleophilic moieties present in DNA
what is the major site of alkylation within DNA?
the N7 position of guanine
what are the toxicities of alkylating agents?
- bone marrow toxicity (neutropenia, thrombocytopenia, anemia)
- mucosal toxicity - oral mucosal ulceration
- nausea and vomiting
- toxic effects on reproductive systems (amenorrhea in women, male sterility)
- increased reisk of leukemia
what are the examples of resistance to alkylating agents?
- decreased permeability or uptake of the drugs
- increased rates of metabolism of the activated forms to inactive species
- enhanced activity of DNA repair pathways
- increased production of glutathione, which inactivates the alkylating agents throguh conjugation
what are the 4 types of alkylating agents?
- nitrogen mustards (mechlorethamine, cyclophosphamide, and ifosfamide)
- Nitrosoureas (carmustine and lomustine)
- Triazenes (dacarbazine and temozolomide)
- Platinum analogs (cisplatin, carboplatin, and oxaliplatin)
how do nitrogen mustards work?
they are bifunctional alkylating agents that undergo spontaneous conversion to active metabolites in body fluids or are enzymatic ally converted to active metabolites in the liver.
what are cyclophosphamide and Ifosfamide?
- prodrugs that must be converted to active alkylating metabolites by hepatic cytochrome P450 enzymes.
- the active alkylating metabolite is phosphramide mustard.
- these drugs can taken orally and have a relatively long plasma half-life compared to other alkylating agents
what are the therapeutic uses of cyclophosphamide?
- most widely used alkylating agent
- has a broad clinical spectrum
- used singly or as part of the combination regimen in the treatment of acute and chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, breast, lung and ovarian cancers
ifosfamide is used to treat
sarcoma and testicular cancer
toxicity of cyclophosphamide and ifosfamide?
- nausea, vomiting, myelosuppression
2. hemorrhagic cystitis
mechanism for hemorrhagic cystitis?
local irritation in the bladder due to toxic drug metabolite (acrolein) in the urine
what can be done to prevent hemorrhagic cystitis?
adequate hydration and administration of MENSA (sodium 2-mercaptoehtane sulfonate), which inactivates acrolein
what are the names of Nitrosoureas?
Carmustine, Lomustine
what are the therapeutic usage of the Carmustine and Lomustine?
they are highly lipohpilic and are able to cross the blood-brain barrier –> b/c of their excellent CNS penetration –> these drugs have been used to treat brain tumors
what are the toxicity of Carmustine and Lomustine?
- cause profound myelosuppression,
- severe nausea and vomiting,
- renal toxicity
- pulmonary fibrosis
what are types of Triazenes?
Dacarbazine and Temozolomide
Dacarbazine is a
prodrug that requires metabolic activation by cytochromes in the liver
Dacarbazine is part of the combination regimen
(ABVD) used for the treatment of Hodgkin’s disease, also used for malignant melanoma
Temozolmide has significant activity against malignant
gliomas, it is the standard agent in combination with radiation therapy
What are 3 Platinum analogs?
cisplatin, carboplatin, oxaliplatin
what are the mechanism of platinum analogs?
- these drugs are inorganic platinum derivatives
- although cisplatin and other platinum analogs do not form carbonium ion intermediates like other alkylaing agents (formally alkylate DNA), they covalently bind to nucleophilic sites on DNA
loading dose creates the conc
for therapeutic
loading dose =
Cp X Vd
platinum analog are converted to active cytotoxic forms by reacting with water to form positively charged, hydrated intermediates that can react with
DNA guanine, forming intrastand and interstand corss-link
Cisplatin has efficacy against a wide range of neoplasms and it is used for the treatment of
- testicular
- ovarian
- cervical
- bladder cancers
what is specifically approved for ovarian cancer?
carboplatin
what is specifically used for treating gastric and colorectal cancer?
oxaliplatin
what are the two important side effects of cisplatin?
- renal toxicity
2. ototoxicity
what is special about the renal toxicity of cisplatin?
it’s the renal tubular damage/necrosis and it’s the dose-limiting toxicity
what is the toxicity of carboplatin?
myelosuppression (thrombocytopenia)
what are two important toxicity of oxaliplatin?
- peripheral sensory neuropathy (cold-induced acute peripheral neuropathy)
- neutropenia
what are antimetabolites?
they are structural analogs of folic acid or the purine/pyrimidine bases found in DNA
b/c antimetabolites inhibit DNA synthesis (S-phase),
they are considered as cell-cycle specific drugs or DNA synthesis inhibitors
what are the two antimetabolites that are folate analogs?
- methotrexate
2. pemetrexed
methotrexate is the most widely used
antimetabolites in cancer therapy
methotrexate is
a folic acid antagonist that inhibits dihydrofolate reductase
what does dihydrofolate reductase do?
converts dietary folate to the tetrahydrofolate form required for thymidine and purine biosynthesis
methotrexate is effective in treating childhood
acute lymphoblastic leukemia (ALL) and choriocarcinoma
methotrexate is also a component of combination therapy regimens for
- Burkitt’s lymphoma
2. carcinomas of the breast, ovary, head and neck and bladder
MTX can not penetrate the CNS,
it is administered intrathecally for treatment of meningeal leukemia and meningeal metastases of a wide range of tumors
high dose MTX is used for
osteosarcoma
what are the significant toxicity of MTX?
- bone marrow toxicity (myelosuppression, spontaneous hemorrhage)
- GI toxicity (oral ulceration, stomatitis)
- renal toxicity (high dose MTX can crystallize in the urine and cause renal damage
- hepatotoxicity
what are the mechanism of resistance to MTX?
- reduced drug uptake by neoplastic cells
- increased production of DHFR (gene amplification)
- decreased affinity of DHFR for MTX
Pemetrexed is a
multi-targeted folate analog
what are the examples of pyrimidine analogs?
- 5-fluorouracil
- cytarabine
- gemcitabine
5-FU is a
pro-drug requireing enzymatic conversion (ribosylation and phosphorylation) into active metabolites (5-FdUMP) to exert its cytotoxic activity.
5-FdUMP inhitibs
thymidylate synthetase and prevents thymidine synthesis
what are the therapeutic uses of 5-FU?
5-FU is given IV b/c of its severe toxicity to the GI tract and rapid metabolic degradation in the gut and liver
5-FU is used as a component of combination therapy for treatment of
breast, colorectal, gastric, head and neck
what is the topical application of 5-FU?
basal cell carcinoma
what is a newer, orally effective form of 5-FU?
capectabine, a prodrug, which is converted to 5’-deoxy-5-fluorouridine
what is the toxicity of 5-FU?
- anorexia and nausea
- mucosal ulcerations
- hand-foot syndrome erythema, sensitivity of the palms and soles can occur
what is an analog of 2’-deoxycytidine?
Cytarabine
what are the 2 significant toxicity of carmustine, lomustine (Nitrosoureas)?
- renal toxicity
2. pulmonary fibrosis
what is 6-mercaptopurine?
purine analogs
what is the primary therapeutic uses of 6-mercaptopurine?
primarily to maintain remission in pts with ALL
what are the two mechanisms of resistance of 6-mercaptopurine?
decreased expression of HGPRT
what is an important drug interaction of 6-MP
allopurinal, which is used to treat hyperuricemia –> allopurinol inhibits xanthine oxidase and thereby increases plasma MP levels
what should be done to pts receiving allpurinol?
decrease the dose of 6-MP
what is 6-MP?
purine analog (pro-drug)
6-MP requires
enzymatic conversion to ribonucelotide by HGPRT
what is one of the pyrimidine analogs which is converted to Ara-CMP by deoxycytidine kinase?
Cytarabine (Ara-C)
what is the most important therapeutic usage of cytarabine (Ara-C)?
AML
what is 5-FU?
pyrimidine analog, a pro-drug which is enzymatically converted into active metabolite 5-FdUMP
5-FU must be given
IV due to rapid metabolic degradation in the gut and liver
toxicity of 5-FU?
hand foot syndrome - erythema, sensitivity to the palms and soles
how can the toxic effect of MTX be prevented?
by leucovorin
what are the two important toxicity of nitrosoureas (carmustine, lomustine)?
renal toxicity, pulmonary fibrosis
