Chemotherapy Flashcards
Growth fraction and mass doubling time
a. it may take months or years for the initial transformed cell to produce a clinically detectable response
b. the time it takes for a tumor to double (mass doubling time) varies
c. tumors depend on diffusion for oxygen and other nutrients, and for the removal of waste products; diffusion is sufficient if
the cells are within 150 m of a capillary
d. as a result of the limitation on diffusion, a steady-state is reached where tumor growth is balanced by tumor death
e. clinically, tumors must be at least 1 cm in diameter (~109 tumor cells) to be detected
Growth fraction and mass doubling time 2
f. one of the critical events for progression of tumor development is the ability of tumors to produce angiogenic
factors such as vascular endothelial growth factor (VEGF) which stimulate new vascular development; due to the formation of new blood vessels which can supply nutrients and oxygen, the tumor may now grow larger
g. often, the tumor will outgrow even its own newly formed vascular supply and the cells in the center of the tumor will die (necrosis); the cells on the outer rim of the tumor are the ones most rapidly proliferating
h. the rapidly proliferating cells constitute the “growth fraction” of the tumor
i. the growth fraction is most susceptible to anticancer drugs
j. the mass doubling time is inversely proportional to the growth fraction
Growth fraction and mass doubling time 3
k. normal tissues with a high growth fraction such as bone marrow, gastrointestinal mucosa, and hair follicles are also the
tissues most damaged by cancer chemotherapeutic drugs; for example, bone marrow has a growth fraction of about 30%, so at doses required to kill tumor cells the bone marrow will also be damaged
l. Note: due to the fact the bone marrow produces granulocytes and platelets, bleeding and infection are two of the limiting complications of chemotherapy
m. small tumors are more susceptible to chemotherapy than large tumors
n. therefore, chemotherapy should be initiated at the earliest stage possible to enhance success
o. Note: surgical removal or radiation reduction in tumor size is often followed by chemotherapy because the remaining cells will be stimulated to enter the proliferating phase; second, metastases also have a high proportion of cells in the growth phase so they will be susceptible to chemotherapy
Total tumor burden
a. if a tumor is large in size, chemo drugs may not be able to penetrate into the tumor at sufficient concentrations to kill
b. the killing of tumor cells by chemotherapeutic drugs follows 1st order kinetics, i.e., a constant proportion of tumor cells are
killed rather than a constant number
c. for example: it would take just as much drug to lower the tumor cell number from 106 to 103 cells (a loss of less than 1 mg
of tissue) as it would to lower the number from 109 to 106 (a loss of 1 g of tissue)
d. at the time of diagnosis, 1012 tumor cells may be present; if you kill 99.9% of these cells with successful chemotherapy, there
will still be 109 cells in the patient
e. the patient may appear to be in remission because 109 are barely clinically detectable; therefore, it is imperative to continue therapy
f. it is only a cure if all tumor cells are killed
Resistance
a. some neoplastic cells are resistant to most anticancer drugs
b. other tumor types can acquire resistance to cytotoxic drugs
c. resistance can be minimized by short-term, intensive, intermittent therapy with combinations of drugs
d. many mechanisms account for drug resistance (change of target, decreased drug penetration, increased drug efflux)
Toxicity
a. most chemotherapeutic drugs have a low TI
b. severe vomiting, stomatitis, alopecia (vomiting may be controlled with antiemetics)
c. myelosuppression
d. treatment-induced tumors: most antineoplastic agents are mutagens - may cause cancer themselves; often these cancers arise 10 or more years after therapy was discontinued and is a particular problem with the alkylating agents (leukemias)
Types of Anticancer Drugs
Alkylating agents Antimetabolites Natural products Hormones and antagonists Targeted agents
Alkylating Agents
Alkylation = covalent binding of alkyl groups to other molecules
Occurs through a positively charged ion, carbonium ion
Binds to RNA or DNA, most often at N7 of guanine
Alkylation is the crucial cytotoxic event
Alkylating agents are NOT cell cycle specific (NCCS)
Mutagens to normal DNA
Alkylating Agents
drugs
- Cyclophosphamide and Ifosfamide
- Nitrosoureas: Carmustine and Lomustine
- Dacarbazine
- Temozolamide
- Cisplatin, Carboplatin, Oxaloplatin
Cyclophosphamide and Ifosfamide
Activated by P450 enzymes to a carbonium ion; also forms acrolein which causes hemorrhagic cystitis which can lead to
fibrosis of the bladder; injection of MESNA (sodium 2-mercaptoethane sulfonate) can minimize the fibrosis due to inactivation of acrolein
Nitrosoureas: Carmustine and Lomustine
Very lipid soluble so useful in brain tumors
Cause delayed BMS (~4-6 weeks)
Cisplatin, Carboplatin, Oxaloplatin
a. are platinum-complexed drugs
b. mechanism of action: similar to the other alkylating agents, these drugs bind to the N7 nitrogen of a guanine in one or both strands of a DNA molecule but don’t form a carbonium ion
Cisplatin, Carboplatin, Oxaloplatin adverse
severe, persistent vomiting occurs one hour
after cisplatin treatment and may continue for as long as 5 days; often, premedication with antiemetics is used; the major limiting
toxicity of cisplatin is nephrotoxicity, which is overcome by infusion of 1-2 L of normal saline prior to treatment; ototoxicity and peripheral neuropathy that is usually distal in a “stocking-and-glove” distribution may also occur; carboplatin only causes mild nausea and vomiting and is not nephrotoxic; the dose-limiting toxicity of carboplatin is myelosuppression; oxaloplatin causes peripheral neuropathy
Antimetabolites
Antimetabolites are structurally related to normal cellular components. They generally interfere with the availability of normal purine or pyrimidine nucleotide precursors by inhibiting their synthesis or by competing with them in DNA or RNA synthesis. Their maximal cytotoxic effects are S-phase specific.
Antimetabolites
- Methotrexate
- 5-Fluorouracil
- 6-Mercaptopurine & 6-Thioguanine
- Cytarabine
Methotrexate (MTX) moa
is structurally related to folic acid and acts as an antagonist to that vitamin by inhibiting dihydrofolate reductase (DHFR) and preventing the conversion of folic acid to
tetrahydrofolic acid; the result of this inhibition is a blockage of the conversion of dUMP to dTMP and inhibition of DNA synthesis; you can use leucovorin rescue (N5 formyl-FH4) which is converted to N5 N10 methylene- FH4 and restore normal DNA synthesis
Methotrexate (MTX) adverse
therapeutic use: cancar & psoriasis & RA
adverse effects: myelosuppression, alopecia, nausea, vomiting, and diarrhea; long-term MTX use may cause hepatic fibrosis (more likely when treating RA or psoriasis)
5-fluorouracil (5-FU) and Capecitabine moa
5-FU is a pyrimidine analog with a stable fluorine atom in place of a hydrogen atom at position 5; intracellularly, it is converted to 5-FdUMP which competes with dUMP for the enzyme thymidylate synthase; 5-FdUMP
binds to thymidylate synthase and inhibits it thereby blocking thymidine production (dTMP) and inhibiting DNA synthesis;
when converted to 5-FUTP it can interfere with RNA function; Capecitabine is a prodrug of 5-FU
5-fluorouracil (5-FU) and Capecitabine adverse
5-FU + leucovorin increases the cytotoxic effects of 5-FU
adverse effects: alopecia, nausea, vomiting, and diarrhea; myelosuppression; after extended infusions, causes “hand-foot syndrome” which is characterized by erythematous desquamation of the palms and soles (more likely with capecitabine than 5-FU)
6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) moa
both must be converted intracellularly to nucleotides by the enzyme HGPRT; inhibit
the first step in de novo purine ring biosynthesis similar to the inhibition exerted by AMP, GMP, and IMP
6-Mercaptopurine (6-MP) and 6-Thioguanine (6-TG) drug interactions
6-MP is metabolized by xanthine oxidase;
concurrent allopurinol use would increase plasma levels of 6-MP (reduce dose by 75%)
Natural Products
- Dactinomycin
- Doxorubicin, Daunorubicin, Idarubicin, Epirubicin
- Bleomycin
- Vinblastine, Vincristine, Vinorelbine
- Taxanes: Paclitaxel
- Etoposide
- Camptothecin analogs: irinotecan and topotecan
Dactinomycin moa
the drug intercalates into the minor
groove of the DNA double helix where it forms a stable complex
with G-C base pairs; the effect of dactinomycin is primarily to
inhibit RNA polymerase but it can also inhibit DNA synthesis
as well; dactinomycin may cause strand breaks
Dactinomycin adverse
adverse effects: major toxicity is bone marrow suppression; nausea, vomiting, diarrhea, stomatitis, alopecia; extravasation
during injection produces localized toxicity
Doxorubicin, Daunorubicin, Idarubicin, Epirubicin moa
all drugs are anthracycline antibiotics
mechanism of action: 1) the drugs intercalate between adjacent base pairs of the DNA helix and cause localized uncoiling which blocks RNA and DNA synthesis
2) inhibition of topoisomerase II
3)generation of oxygen radicals: cytochrome P450 reductase, found in nuclear membranes, catalyzes the reduction of anthracyclines to semiquinone free radicals (Fe+++-anthracycline complex) which can then produce superoxide ions and hydrogen peroxide; superoxide and hydrogen peroxide can cause DNA strand breaks
Doxorubicin, Daunorubicin, Idarubicin, Epirubicin radicals
tissues are protected from these radicals by superoxide
dismutase and glutathione peroxidase, but some tissues
such as the heart and tumor tissue are generally low in these protective systems; therefore, the anthracyclines have
cardiotoxicity as an adverse effect (presents acutely as
arrhythmias and chronically as dilated cardiomyopathy)
Doxorubicin, Daunorubicin, Idarubicin, Epirubicin adverse
adverse effects: irreversible, dose-dependent cardiotoxicity
(free radicals); in combination with irradiation of
the thorax, cardiotoxicity risk is increased; bone marrow
suppression; nausea, vomiting, diarrhea, stomatitis; alopecia is usually severe
dexrazoxane (Zinecard): metal chelator that blocks the reaction of iron with anthracyclines; given prior to doxorubicin to prevent cardiomyopathy
