Flashcards in Chemotherapy of Neoplastic Diseases Deck (33):
What are the various cancer treatment modalities?
What are the principles of cancer chemotherapy?
The purpose of treating cancer with chemotherapy is to stop cancer cell from multiplying, invading, metastasizing and ultimately killing the host (patient)
What are the indications for chemotherapy?
Four main clinical settings:
1. Primary induction treatment
2. Neoadjuvant treatment
3. Adjuvant treatment to local methods of treatment
4. Site directed chemotherapy
What is primary chemotherapy?
Chemo administered as the primary treatment in patients who present with advanced cancer for which no alternative treatment exists
--advanced metastatic disease
-goals: relieve tumor related symptoms, improve overall quality of life and prolong time to tumor progression
What is Neoadjuvant chemotherapy?
Use of chemo in patients who present with localized cancer for which alternative local therapies (Surgery), exist but which are less than completely effective
--goal: reduce the size of the primary tumor so that surgical resection can be made easier
--additional chemo is given after surgery has been performed
What is Adjuvant chemotherapy?
Use of chemo after local treatment modalities (surgery) has been performed
--goal: reduce the incidence of both local and systemic recurrence and to improve overall survival of patients
--examples: alpha interferon: in patients with primary malignant melanoma or antihormonal agents in postmenopausal women with estrogen receptors positive breast cancer
What is site directed chemotherapy?
Direct instillation into sanctuary sites (intrathecal or peritoneal)
Regional Perfusion of the tumor (intra arterial)
What is growth fraction?
Percentage of actively dividing cells at any given point in time
--high growth fraction neoplasms (leukemia and lymphoma) are more sensitive to chemotherapeutic drugs
--low growth fraction timor (Solid tumor) are less responsive to chemotherapy
With rare exceptions (choriocarcionoma and burkitt's lymphoma) combination chemotherapy is the standard approach in the management of many tumors because...?
1. It provides maximal cell kill within the range of toxicity tolerated by the host for each drug
2. Some combinations of anticancer drugs appear to exert synergistic effect
3. Drug combinations are effective against a broader range of cell lines
4. May prevent or slow the subsequent development of cellular drug resistance.
What is the log kill hypothesis?
Proposes that the action of cytotoxic drugs follows first order kinetics
--a given dose kills a constant fraction of a tumor cell population (rather than a constant number of cells)
--repeated doses of chemo are required to eradicate the tumor cells
Give an example, using Leukemia, of the log kill hypothesis
A dx of leukemia is made when there are about 10^9 leukemic cells. If treatment leads to a 99.99999% kill (a 5 log kill) this would induce a clinical remission of the neoplasm associated with symptomatic improvement
---there would still be 0.0001% of 10^9 cells (10^4 tumor cells) remaining in the body
In common bacterial infections, a 3 log reduction in microorganisms may be curative because the immune system can eradicate residual bacterial. Tumor cells are not as readily eliminated. Hence?
Repeated doses of chemotherapy must be used for total cells kill
One of the limitation of chemotherapy is toxicity to normal cells. Chemo exerts their effect on cell proliferation, why?
Because proliferation is a characteristic of many normal cells as well as cancer cells, most chemo agents have toxic effects on normal cells, particularly those with rapid rate of turnover, such as bone marrow and mucous membrane cells.
What are the common adverse effects of the toxicity of chemo to normal cells?
Nausea and vomiting (treated with 5HT3 blockers and NK1 inhibitors)
Myelosuppression (Filgrastim, a granulocyte colony stimulating factor, is used to treat neutropenia)
Another limitation of chemotherapy is resistance to cytotoxic drugs. What is primary resistance and acquired resistance?
1. Primary resistance: no response to the drug on the first exposure
2. Acquired resistance: single drug resistance (Due to increased expression of one or more genes) and multidrug resistance (MDR)(resistance emerges to several different drugs after exposure to a single agent)
--P-glycoprotein (permeability glycoprotein) is the most important efflux pump responsible for multidrug resistance. Hence the other name for this pump is multidrug resistance protein 1 (MDR1)
Moving onto the anti-cancer drugs. They can be classified into what?
Cell cycle -specific drugs:
--anti-neoplastic drugs that exert their action only on cells traversing the cell cycle
Cell cycle- non specific drugs:
--can kill tumor cells whether they are cycling or resting in the G0 compartment (although cycling cells are more sensitive)
What are the cell cycle specific agents?
1. Antimetabolities (S phase)
2. Bleomycin (G2-M phase)
3. Microtubule Inhibitors (M phase)
4. Epipodophyllotoxins (S-G2 phase)
5. Camptothecins (S-G2 phase)
What are the cell cycle non specific agents?
1. Alkylating agents
2. Platinum coordination complexes
3. Antitumor Antibiotics (Except bleomycin)
In general cell cycle specific drugs are most effective in hematologic maligancies and other tumors in which a large proportion of the cells are proliferating or are in the growth fraction. What about cell cycle non specific drugs?
Useful in low growth fraction solid tumors as well as in high growth fraction tumors
--in all instances, effective agents sterilize or inactive tumor stem cells, which are often only a small fraction of the cells within a tumor.
In addition to the cell cycle specific agents and cell cycle non specific agents what are the other anti cancer drugs?
Platinum coordination complexes
Signal Transduction Inhibitors
First set of drugs are the Antimetabolites (cell cycle specific agents s phase). What does this class include?
1. Folate Analogs:
2. Purine Analogs:
--6-mercaptopurine and 6-Thioguanine
3. Pyrimidine analogs:
---Fluoropyrimidines: 5-Fluorouracil and Capecitabine
---Deoxycytidine Analog: Cytarabine and Gemcitabine
First up are the Folate Analogs (antimetabolite). The only drug in this category is methotrexate (MTX). What are the pharmacokinetics?
IV, Intrathecal and Oral Route
Renal excretion is the main route of elimination and is mediated by glomerular filtration and tubular secretion
If MTX is used in the presence of drugs such as aspirin, NSAIDs, penicillin, and cephalosporins be careful because these agents inhibit the renal excretion of MTX
What is the MOA of MTX (anti-metabolite)?
Intracellular conversion to MTX polyglutamates
--process is catalyzed by the enzyme folylpolyglutamate synthase (FPGS)
MTX polyglutamates are selectively retained within renal cancer cells, and they bind and inhibit dihydrofolate reductase (DHFR) enzyme. This results in inhibition of the synthesis of tetrahydrofolate (THF) which is involved in denovo synthesis of (deoxythymidylate nucleotides and purine nucleotides)
Inhibition of these metabolic processes interferes with the formation of DNA, RNA and key cellular proteins.
In regards to MTX what is Leucovorin rescue?
Leucovorin (5-Formyl derivative of tetrahydrofolic acid) rescue is used in conjunction with high dose MTX therapy to:
--rescue normal cells from undue toxicity
---overcome accidental drug overdose
What are the clinical applications of MTX?
Breast cancer, head and neck cancer, osteogenic sarcoma, bladder cancer, choriocarcinoma, primary central nervous system lymphoma and non-hodgkin;s lymphoma
Also used for non neoplastic conditions such as:
--ectopic pregnancy and medical abortion
--RA, psoriasis, inflammatory bowel disease and vasculitis
What is the Mechanism of Resistance for MTX?
Decreased drug transport via the reduced folate carrier or folate receptor protein
Decreased formation of cytotoxic MTX polyglutamates
Increased levels of the target enzyme DHFR through gene amplification and other genetic mechanisms
Altered DHFR protein with reduced affinity for MTX
Decreased accumulation of drug through activation of the multidrug resistance transporter P170 glycoprotein may also result in drug resistance.
Finally what are the adverse effects of MTX?
--stomatitis, mucositits, n/v/d
--some of these can be reversed by Leucovorin, which is taken up more readily by normal cells than by tumor cells
2. Pulmonary Fibrosis
3. Neurotoxicity: occur with IT admin, causes meningismus and an inflammatory response in the CSF, seizures, coma and death. not reversed with Leucovorin
4. Hepatotoxicity: acute, reversible elevation of liver enzymes, hepatic fibrosis and cirrhosis
5. Nephrotoxicity: in high doses MTX accumulates and obstruct the renal tubular lumen leading to renal damage.
The next antimetabolite drug are the Purine Analogs. The first purine analog is 6-Mercaptopurine. What are some features?
Orally -- widely distributed throughout the body except CSF
Inactivated by xanthine oxidase (allopurinol is an xanthine oxidase inhibitor and is used in the tx of acute leukemias to prevent development of hyperuricemia that often occurs with tumor cell lysis)
Allopurinol with 6-MP would result in increased levels of 6-MP, thereby leading to excessive toxicity. So the dose of 6-MP must be reduced
6-MP is also inactivated by thiopruine methyltransferase (TPMT) -- ppl with partial or complete deficiency of this enzyme are at increased risk for severe toxicities so dose needs to be reduced
What is the MOA of 6-Mercaptopurine?
--analog of hypoxanthine
Converted to 6-MP ribose phosphate (6-MPRP also known as TIMP) by the salvage pathway enzyme, HGPRT
TIMP inhibits Phosphoribosyl pyrophosphate amidotransferase enzyme: which catalyzed the rate limiting step of the de novo purine ring biosynthesis.
TIMP also blocks formation of AMP and GMP from IMP
The monophosphate form is metabolized to the triphosphate form, which can then be incorporated into both RNA and DNA leading to dysfunctional DNA and RNA.
What are the clinical applications, mechanism of resistance and adverse effects of 6-MP?
--childhood acute leukemia (ALL)
Mechanism of Resistance:
--inability to bio transform 6-MP to the nucleotide because of low HGPRT
--increased metabolism of the drug to thiouric acid
--bone marrow suppression
The other antimetabolite purine analog is 6-Thioguanine. What are the pharmacokinetics?
6-TG is inactivated by deamination --means significant interaction between 6-TG and allopurinol does not occur
6-TG is also metabolized by the enzyme thiopurine methyltransferase (TPMT), in which a methyl group is attached to the thiopurine ring. Patients who have partial or complete deficiency of this enzyme are at increased risk for developing severe toxicities so dose needs to be reduced
What is the MOA for 6-Thioguanine?
Converted to the nucleotide thioguanosine monophosphate (TGMP) by HGPRT
--inhibits the synthesis of the purine nucleotides by inhibiting PRPP amidotransferase
--inhibits the phosphorylation of GMP to GDP by Guanylate kinase enzyme
--can be converted to TGTP and dTGTP which incorporate into RNA and DNA