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Harvard-MIT Division of Health Sciences and Technology
HST
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Donald Kufe

1

HST-151

Principles of Clinical Cancer Chemotherapy and Drug Resistance
Cancer Mortality: 2000 = 553,091; Est
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Curative
• Acute Lymphocytic Leukemia, Hodgkin’s Disease, Diffuse Histiocytic
Lymphoma, Burkitt’s Lymphoma
• Testicular Cancer, Choriocarcinoma
• Wilms’ Tumor,* Ewing’s Sarcoma,* Embryonal Rhabdomyosarcoma*
2
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Major Therapeutic Benefit (Short of Cure)
• Head and Neck Cancer, Cervical Cancer, Metastatic Breast Cancer, Ovarian
Cancer
• Soft Tissue Sarcoma
• Nodular Lymphomas, Chronic Leukemias
• Insulinomas
4
...


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HST-151

Acute Lymphocytic Leukemia: Induction of Chemotherapy
1
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3
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First Order Kinetics
Host Toxicity
Selectivity
Combination Chemotherapy
1
...
This means that the same dose which decreases the tumor burden from
106 to 103 cells will be needed to decrease the burden from 103 to 100 cells
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1

10 3

0
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001

10 1
10 0

Cell Number

10 6

0
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9% effective will
still leave 103 cells untouched
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Treatment should aim for 10-1 cells or less remaining to ensure a high
percentage of cures
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• Top solid line = moderate, infrequent dosing of chemotherapy which prolongs
survival but results in recurrent symptoms and eventual death
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Cell kill exceeds regrowth and treatment is
sufficiently long to sterilize tumor (patient is cured)
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4

HST-151

2
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Both curves are steep, and displacem ent of the toxicity curve to the right reflects
the therapeutic index (median toxic dose/median effective dose) which is usually low for
antitumor agents
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1

1

10

100

Drug Concentration

1000

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HST-151

3
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Each chemotherapy course causes a similar destruction of
normal bone marrow and tumor cells, Rate of recovery of normal bone marrow,
however, is greater than that of tumor cells
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No
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Combination Chemotherapy
Combining drugs with different mechanisms of action and different dose-limiting
toxicities can produce a bigger therapeutic effect at maximally tolerated doses of all
drugs
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Cell cycle active, phase specific
2
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Non-cell cycle active
Mitotic Cycle

7

HST-151

Cell Cycle Active, S Phase Specific
ANTIMETABOLITES
Mechanisms
• incorporation of nucleotide analog in DNA or RNA, resulting in abnormal
nucleic acids
• inhibition of certain enzymes involved in nucleotide biosynthesis
Examples:
• Pyrimidines
Uracil: 5-fluorouracil (5-fluoro-2’-deoxyuridine)
Thymine: 3’-azido-3’-deoxythymidine
Cytosine: Cytosine arabinoside; 5-azacytidine
• Purines
Adenine: 6-mercaptopurine
Guanine: 6-thioguanine
ANTIFOLS (METHOTREXATE)

Mechanism: competitive inhibition of dihydrofolate reductase, necessary for generation

of methyl donors required for thymidine synthesis
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e
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COLI, ERWINIA)
Mechanisms
• l-asparaginase converts asparagine to aspartate and NH3
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• Drug has activity in acute lymphocytic leukemia
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Toxicity
• Hypersensitivity (urticaria, anaphylaxis)
• Pancreatitis
• Hepatotoxicity

11
Classification by Important Toxicity
1
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Hepatic
• 6-Mercaptopurine (cholestatic jaundice)
• L-asparaginase (abnormal liver function tests)
• Anthracyclines (dependence on biliary excretion)
3
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Neurotoxicity (paresthesias)
• Plant alkaloids
5
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Cardiac
• Anthracyclines (chronic cardiomyopathy)
• Cyclophosphamide (acute arrhythmias)
7
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SIADH
• Vincristine
• Cyclophosphamide

HST-151

12

HST-151

Requirements for Combination Chemotherapy
1
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Each drug should have
• A different mechanism of action
• A different dose-limiting toxicity
3
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Mustard
VCR
PRED
Procarbazine
MOPP

Toxicity
Marrow
Neuropathy
Steroid
Marrow

% Full Dose
100
100
100
100
60/100/100/60

% Remission
10
5
5
15
70 (50% cure)

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HST-151

M-BACOP – Diffuse Lymphoma
Drug(s)
MTX-CF
Bleo
Adriamycin
Cyclophosph
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Tumor Host Resistance
A
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Location of tumor cells
• Pharmacologic sanctuary
• Blood supply to the anatomical region
• Extravascular distance for drug diffusion
• Drug metabolism by extracellular enzymes and normal cells that surround the
tumor
2
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Growth Characteristics
Mean volume doubling times for certain human tumors
Tumor
Testicular Carcinoma
Ewing’s Sarcoma
Non-Hodgkin’s Lymphoma
Osteogenic Sarcoma
Hodgkin’s Disease
Fibrosarcoma
Colonic Adenocarcinoma
Pulmonary Adenocarcinoma

Doubling Time (Days)
21
22
25
34
36
48
95
154

Volume Doubling (Days)

There is an inverse correlation between volume doubling time and response to
chemotherapy (slower growth = worse response)
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B
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Altered absorption, distribution or excretion of a drug so that less reaches the tumor
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Increased synthesis of enzymes from non-malignant cells which inactivate the drug
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Increased sensitivity of normal tissues to the effect of a drug
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Cellular Resistance
A
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B
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1
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Drug
exposure provides the pressure for selection of a resistant cell population
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The frequency of drug resistant mutants is increased by antitumor agents which are
also mutagens
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demonstrated that treatment with chemical
mutagens and single-step selection results in the emergence of tumor cells resistant to
fluoropyrimidines
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16

HST-151

C
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Acquired Methotrexate Resistance
Acquired MTX resistance has been attributed to a variety of mechanisms
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Altered transport
2
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• MTX-PGs have a higher affinity for DHFR, cause prolonged inhibition of
DNA synthesis and increase cytotoxicity
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Increased production of DHFR (gene amplification)
• Abnormal homogeneous staining regions (HSRs): sites identified in MTX
resistant cells which represent amplified DHFR genes on chromosome 2
(mouse) and 5 (human)
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• Double minute chromosomes (DMs): small chromosomes of varying size
without centromeres, usually occurring in pairs
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Gene
amplification on the double minute chromosome is thus unstable in the
absence of selecting agents
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Altered DHFR
• DHFRs in some resistant cells have a low affinity for MTX
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This
mutation (arginine for leucine) decreases both binding of MTX and function
of the enzyme
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Multidrug or Pleotropic Resistance
1
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The affected drugs
include a wide spectrum: anthracyclines, vinca alkaloids, actinomycin,
podophyllotoxins
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Resistant cells have an impaired ability to accumulate and retain drug
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3
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• Drug resistance is related to the amount of P-glycoprotein
• Cells which regain drug sensitivity no longer express the membrane
alteration
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• Transfer of multidrug resistance with a cDNA coding for the P-glycoprotein
demonstrates that overexpression of this single gene is sufficient to confer the
resistance phenotype
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The P-glycoprotein or MDR1 gene is a member of a small family of genes
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5
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The degree of amplified DNA fragments correlates
with the degree of drug resistance
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6
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There are two similar domains with cytoplasmic
sites that bind ATP
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P-glycoprotein
is primarily expressed on plasma membranes while smaller amounts have been
detected in the ER and Golgi membranes
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Vinblastine photoaffinity analogs bind to the P-glycoprotein, and binding is
competitively antagonized by unlabeled vinblastine and anthracycline
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Moreover, vinblastine is transported by an ATP-dependent process
through membranes that contain P-glycoprotein
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The P-glycoprotein is also homologous to bacterial transport proteins which are
involved in ATP-dependent transport of specific molecules, particularly hemolysin,
through the bacterial inner cell membrane
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High levels of MDR1 gene expression have been found in liver, colon, small
intestine, kidney, adrenal cortex and adrenal medulla
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MDR1 RNA levels are usually high in those
cancers derived from normal tissues which themselves have high MDR1 expression
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Intrinsic multidrug resistance appears to be related to persistent expression of a gene
involved in normal cellular function
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Mechanisms of de
novo resistance to therapy in tumors associated with increased carcinogen exposure
(colon, lung cancer) may therefore be similar to those associated with acquired
resistance to anti-neoplastic agents
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Drugs such as verapamil, diltiazem and quinidine have been found to overcome
multidrug resistance in cell culture and in some animal experiments
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Verapamil competes with vinblastine for binding, suggesting that drug binding
to the P-glycoprotein is a necessary step in the process of drug resistance
Other agents that reverse P-glycoprotein-mediated multidrug resistance include
steroids and steroid antagonists (progesterone and tamoxifen) and reserpine
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11
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A
Phase I-II study failed to demonstrate a potentiation of doxorubicin therapy with
verapamil in eight drug-resistant ovarian cancer patients
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The three responding patients had P-glycoprotein
positive tumors
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Myelosuppression was not increased in this trial
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Other clinical studies are underway using
amiodarone and quinidine as inhibitors of P-glycoprotein mediated resistance
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Acquired Resistance to Alkylating Agents
Prolonged exposure of human cells to alkylating agents has resulted in a maximum of 1015 fold resistance
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Alkylating agents therefore more
closely resemble X-irradiation where significant resistance has not been demonstrated
with repetitive treatment
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RC, Kufe DW, Pollack RE, Weichselbaum RR, Holland JF, Frei III E
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BC Decker, Inc

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