Cancer drugs Flashcards
(157 cards)
1
Q
Cancer treatment depends on what 5 things
A
Type of cancer, Grade, Stage
Known biological behavior
Other factors
2
Q
Type of cancer
A
Cytology/biopsy Radiographic appearance (i.e. OSA)
3
Q
Grade
A
Degree of differentiation (histopath)
Mitotic index
Other markers (i.e. AgNor score)
4
Q
Mitotic Index
A
Number of mitoses seen in 10 high powered fields
Higher MI= higher liklihood metastasis
5
Q
Special way of scoring mast cell tumors
A
AgNor scores (Argyrophilic) is silver staining for nucleolar organizing regions within individual nuclei
higher AgNor score = higher likelihood metastasis
6
Q
Stage **on exam
A
Is there metastasis present? Or is it local? What is the overall tumor LOAD?
7
Q
Known biological behavior – example= OSA
A
OSA thoracic rads- most have no visible pulmonary metastasis at TIME of diagnosis
90% of canine OSA patients will die within 1 year of diagnosis (pulmonary metastasis)
CONSIDER SYSTEMIC DISEASE treatment
8
Q
What are “other factors” that cancer treatment depends on
A
Oncogenes
receptors
anatomic location
mdr1 status etc
9
Q
Three primary methods of cancer treatment
A
Localized Disease- Surgery, radiation therapy
Systemic Disease- Chemotherapy
10
Q
What are characteristics of cancer cells not shared by normal cells?
A
Rapid proliferation (enzymes, substrates related to DNA synth/structure/fxn)
Angiogenesis (cancer cells need blood supply)
Ability to manipulate immune cells and microenvironment
11
Q
Stages of the Cell Cycle
A
M, G1 (if not dividing go into cell G0), S, G2
12
Q
how long does M stage take
A
1-7 hours (small % of cell cycle)
13
Q
M stage- what drug works here
A
Vinca alkaloids
give once a week
14
Q
how long does G1 stage take
A
7-170 hours
15
Q
What happens in G1 phase (1st gap phase)
A
RNA transcription (produce mRNA) Protein synthesis (required for DNA replication)
16
Q
What drugs work in G1 phase
A
not that many ..
17
Q
How long does S phase take
A
8-30 hours
18
Q
What happens in S phase
A
DNA synthesis in preparation for chromosomal duplication (8-30 hours)
Making DNA so have big nuclei, high metabolic rate and energy requirements
19
Q
What drugs work in S phase
A
Antimetabolites
20
Q
how long does G2 phase last
A
1-4 hours
21
Q
what happens in G2 phase
A
2nd gap phase
It is a pause prior to mitosis - likely organization of proteins and cellular machinery required for mitosis
22
Q
G0 phase- how long
A
variable, can be years
23
Q
G0 phase– what cells do not re-enter cell cycle?
A
Neurons, muscle cells do not re-enter cell cycle
Hepatocytes normally do not re-enter after maturity, but can readily do so! (can sit there for years, then start to grow)
24
Q
Chemotherapy and cell cycles
A
Can be cell cycle non specific (kills non replicating cells as easily as replicating cells), Cell cycle specific, and phase specific ?
not very phase specific ?
25
Fractional cell kill- define
Chemotherapy kills a constant FRACTION of cells, not a constant NUMBER of cells
Can be 10% to 99.9%
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small tumor vs tumor at time of dx
```
small tumor (1 gram) has 1 billion cells (10^9)
tumor at time of dx is about 10 grams (10 billion cells)
```
27
how many cells = incompatible with human lfie
1 kg tumor = 10^12 cells
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1 gram tumor has undergone ___ doubling times if it started from 1 cell
30
29
To get from 10 grams (Diagnosis) to 1 kg (Incompatible with life), only ___ more double times required
10
30
1 gram of tumor is how many cells
1 billion
31
Dr Mealey's drug for fractional cell kill
Mealeymicin, theoretical antineoplastic agent would have 90% cell kill fraction
32
Mealeymicin Fractional cell kill -- see charts
..
33
Chemotherapy is limited by what
By host toxicity
**Dose and interval
By development of drug resistant cells
34
Chemo-- what interval is best
3 week intervals at best, allows repopulation of tumor cells
35
What are four ways of Chemo resistance?
Altered Target
Inactivation of drug
Failure to reach target
Failure to undergo apoptosis
36
How does the target get altered?
```
Chemo drugs(such as Doxorubicin) target DNA topoismerase enzymes (essential for DNA replication)
MUTATIONS in enzyme can occur in tumor cells
```
37
How do chemo drugs get inactivated?
Detoxifying mechanisms in normal cells are also present in neoplastic cells (such as Glutathione S transferase system "detoxified" alkylating agents)
These detoxifying mechanisms can be OVER expressed
i.e. Tumor cells that over express GST --> more detoxification --> resistant to alkylating agents like Cyclophosphamide
38
How do chemo drugs fail to reach their target?
Transport pumps (P Glycoprotein) pumps CHEMO DRUGS out of cell --> Multidrug resistance
MDR1 phenotype- not in collies
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Cross resistance to several entire classes of chemo drugs
Doxorubicin
Vincristine
Vinblastine
Taxanes
40
Which tissues are already more resistant
Pulmonary parenchyma, hepatocellular ?
41
How do tumors contribute to a chemo drug's ability to kill cells by inducing apoptosis?
Tumors overexpress BCL-2 (Anti-apoptosis)
| Tumors with mutations in Tumor suppressor gene-p53 can be resistant to apoptosis
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4 different responses to chemo
Complete response, partial response, stable disease, progressive disease
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Complete response
Resolution of clinically apparent disease (palpable masses, radiographic disease, leukemic cells, paraneoplastic syndromes)
At least 1 month
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Partial response
Reduction of tumor dimensions by at least 50% for 1 month duration
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Stable disease
No change to <50% reduction in tumor dimensions
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Progressive Disease
Growth of lesion or appearance of new lesions
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RECIST
Response Evaluation Criteria in Solid Tumors
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Recist criteria based on what?
Based on one dimension
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Recist criteria with the 4 responses
Complete response- tumor no longer detectable
Partial response - greater than 30% decrease in longest dimension
Stable Disease- less than 30% decrease, or less than 20% of tumor growth
Progressive Disease - more than 20% increase in longest dimension observed
50
Clinical trials -- how does it work?
NIH and pharmaceutical companies-- screen compounds against a panel of tumor cell lines --> efficacacious compounds tested in rodents first --> efficacy --> Phase 1 clinical trials
51
Phase 1 clinical trial
recruit patients with advanced tumors, with no effective treatment --> determine MAX tolerated dose --> if ANY efficacy --> phase II
52
Phase 2 clinical trial goal
determine which tumor type the drug is efficacious for
again, recruit patients with advanced tumors of various types --> efficacy towards a tumor TYPE --> phase 3
53
Phase 3 clinical trial goal
to determine if drug candidate + other drugs = improvement over "gold standard"
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Vetmed drug screening vs FDA approved drugs
for vetmed, drugs just need to be "safe" -- not necessarily efficacious!
55
Body Surface Area (BSA) correlates with what 3 things
CO, GFR, BMR
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BSA does not correlate better with what
Bone marrow stem cell turnover
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BSA-- see charts with the Meters squared
..
58
BSA equation
BSA in M^2 = (km x W ^2/3) / 10^4
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Body weight vs BSA-- body weight better correlates with what
with myelosuppression
Dogs < 10kg (less weight) more likely to develop myelosuppression if based on BSA (vs body weight)
60
Common toxicities- BAG
Bone marrow
Alopecia and Anaphylaxis
GIT
also infertility (more problematic in people)
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Bone marrow suppression- which cells are affected
Neutrophils first, then platelets and RBCs
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Alopecia -- dose this affect pets as much?
not as much since dogs and cats do not have constantly growing hair (hair follicles = rapidly dividing cells)
some breeds more affected (Poodles, English sheepdog)
63
GI toxicities
Anorexia, Nausea, VD
| less common in veterinary patients
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Cisplatin and GI toxicities
Premed to prevent nausea (Cisplatin = #1 vomit inducer)
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Lomustine and GI toxicities
Give at bedtime to allow sleeping through nausea
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Doxorubicin and GI toxicities
May cause colitis
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Infertility
Males and females, congenital malformations can occur in offspring
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What should be discussed with owner about the Maximum tolerated dose
Goals- Palliation (tolerate fewer side effects) vs Cure (tolerate more side effects)
69
What are some guidelines for chemotherapy
Not used empirically (can't just use one drug for everything)
Agent must have efficacy for tumor
Monitor with objective criteria!!!!! (i.e. US bladder each time, rads for lung nodules)
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Chemo drug toxicity-- 3 things
Carcinogenic
Mutagenic
Teratogenic
71
Chemo drug- safety issues
animal waste may contain active drug
Preparation-- low traffic area with safety hood, gloves, closed system/chemo pins
Do not crush pills
Incinerate trash
72
Alkylating agents- 3 MOA
Interferes with DNA replication (several mechanisms)
i.e. through alkylating --> abnormal bases --> repair enzymes can't recognize --> DNA is fragmented
i. e. Alkylated bases form cross bridges --> prevent DNA separation for synthesis/transcription
i. e. Alkylated Guanine pairs with Thymidine --> Mutations (instead of AT, CG)
73
4 examples of Alkylating agents
```
CCLM
Cyclophosphamide (cytoxan)
Chlorambucil
Lombustine
Melphalan
```
74
Cyclophosphamide toxicity - BAG
BAG with nadir at 7-14 days
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Cyclophasmadide main toxicity concern
Sterile hemorrhagic cystitis
* Metabolite (acrolein) accumulates in urine
* irreversible
76
Cyclophosphamide- prevention of toxicity
More water intake and frequent voiding (can use Prednisone or a diuretic)
**don't prescribe if owner can't take them out often
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Lombustine toxicity
BAG
Chronic neutropenia or thrombocytopenia (nadir 1-3 weeks)
LIVER, renal, lung toxicity long term!!
78
Chlorambucil toxicity and use
BAG
| Used instead of cyclophosphamide (if pts don't tolerate it)
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Lymphoma protocols
Primary use = Cyclophosphamide
| Also lombustine; chlorambucil (low grade lymphomas)
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Mast cell tumor or Histiocytic sarcoma-- drugs
Lombustine
81
Alkylating agents- DOSING
METRONOMIC = given at low constant dose to suppress angiogenesis
82
Mitotic inhibitors- MOA
Bind microtubules --> interfere with cell division
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Mitotic inhibitors name 2 examples
Vinca Alkaloids
| Taxanes
84
Vinca alkaloids - 2 drugs
Vincristine (Oncovin)
| Vinblastine
85
Taxanes- name a drug
Paclitaxel (from pacific yew tree)
86
Vinca alkaloids-- toxicity (name 3)
BAG (Vinblastine more bone marrow suppressive than vincristine)
Vesicant (one stick protocol)
Neurotoxicity (irreversible) i.e. hum
ans feel tingly fingers
87
Paclitaxel toxicity
BAG
| Also removed from market Feb 2017!
88
Mitosis Inhibitors- clincal uses of vincristine
Lymphoma protocols
| TVT
89
Vinblastine uses
Canine mast cell tumor, lymphoma
90
Paclitaxel uses
Mammary tumors, ScCMA
91
Mitosis inhibitors- route of admin
Injectables only, NO ORAL
92
Antibiotics MOA
```
Intercalation into DNA
Inhibits Topoisomerase (this enzyme unwinds DNA for transcription)
```
Interferes with DNA and RNA synthesis
93
Antioiotics-- 2 examples
Doxorubicin
Mitoxantrone
"red death or blue thunder:
94
Antibiotics Toxicity - BAG
BAG with nadir at 7-10 days
95
Antibotics toxicity - heart
cumulative cardiac toxicity (Doxorubicin) that is irreversible!!
96
Antibiotics toxicity- GI
Colitis (hemorrhagic)
97
Antibiotics toxicity-- vesicant
DOXORUBICIN
SEVERE tissue reaction if SQ
ONE STICK PER VEIN
98
Antibiotics- clinical use
Lymphoma protocols
| Sarcomas (Doxo is best because broad spectrum)
99
Antibiotics- newer analogues efficacy
May be less cardiotoxic, but not as efficacious as doxorubicin
100
Antibiotics- bleomycin
Electrochemotherapy mostly
101
Platinum compounds MOA
Intra-strand cross link DNA interfering with RNA synthesis + DNA replication
102
Platinum compounds- 2 examples
Cisplatin
| Carboplatin
103
Platinum compounds- toxicity (BAG)
Cisplatin is EMETOGENIC so patients need pre treatment ANTI EMETICS
104
Carboplatin- nadir
Bimodal at day 6 and 15 (less predictable)
105
Platinum compounds- nephrotoxicity
Cisplatin! Need diuresis (pre, during, post TX)
| Carboplatin = less nephrotoxin
106
Platinum compounds- ears and resp
Ototoxicity
| Respiratory:
*Cisplatin --> Fatal pulmonary edema in cats
carboplatin safer in cats
107
Cisplatin is agent of choice for _____ but largely replaced by ____ due to decreased toxicity and ease of admin
Osteosarcoma
| Carboplatin
108
Other uses of cisplatin
Carcinomas
| Intralesional in EQUINE sarcoids
109
Antimetabolites MOA
Interfere with purine and pyrimidine synthesis and incorporation into DNA
110
Antimetabolites- 4 examples
CAM 5FU
Cytosine arabinoside
Azathiprine
Methotrexate
5 Fluorouracil
111
Methotrexate BAG
Nadir at 6-9 days
112
What makes Methotrexate have drug interaction potential
Highly protein bound
113
5FU toxicity
BAG
| CENTRAL NEUROTOXICITY = FATAL IN CATS !!!
114
Azathioprine toxicity
BAG- lower frequency in dogs
| MYELOSUPPRESSION - avoid in cats
115
Cytosine arabinoside - BAG
Nadir in 1-14 days (can drop rapidly in just a day!)
116
Clinical use of Methotrexate
older UW madison protocol for lymphoma (not used much anymore)
117
Clinical use of 5FU
Carcinomas!!!!
118
Clinical use of Azathioprine
Immune mediated disease
119
Clinical use of cytosine arabinoside
Canine non infectious encephalitis (Neuro department!!)
| Acute leukemia and lymphoma in horses
120
L asparaginase MOA
Deprives tumor of asparagine -> inhibits PR synthesis -- KILLS LYMPHOCYTES QUICKLY
good in the short term
121
L asparaginase toxicity
Allergic reactions (pretreat with Antihistamines) "asparaginase, allergies...ASPPPP and PPPPancreatitis"
Relatively BM sparing except if used with Vincristine
Pancreatitis
+- Vomiting
122
Clinical use of L asparaginase
Lymphoma
123
L asparaginase route of admin
Give SQ
| DO NOT GIVE IV --> Anaphylaxis
124
NSAIDS MOA (proposed) Name 4
COX2 may be overexpressed in many tumors --> block COX2
| NSAIDS may enhance APOPTOSIS, decrease tumor invasiveness, block angiogensis
125
Piroxicam- current usage
rarely used now (COX2 selective agents may be better)
| Used for Transitional cell tumors and paillation of other tumor types
126
Piroxicam-- toxicity
NSAID so GI ulcers, renal
127
Tyrosine Kinase Inhibitors-- MOA
Inhibit cell signaling (proteins involved in cell replication)
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Tyrosine Kinase Inhibitors-- name an agent used in vetmed
Toceranib phosphate (Palladia)
129
Palladia usage
1st FDA approved drug for treating cancer in vet patients
Grade II and III mast cell tumors
130
Palladia-- what is important to remember
92% protein bound, so AVOID NSAIDS
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Besides Palladia, what is another Tyrosine Kinase inhibitor
Masitinib (Kinavet-CA1)
Also treats Grade 2 and 3 mast cell tumors
and protein bound
CURRENTLY OFF THE MARKET IN USA
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Tyrosine Kinase Adverse effects
Neutropenia
GI ulcers (AVOID NSAIDS)
Vasculitis (Thromboembolic disease)
PLN
basically with TK-I, think 3 blood things and PLN
133
Canine melanoma vaccine MOA
DNA vaccine: HUMAN tyrosinase (human form so dogs can respond)
Tyrosinase is present on surface of melanoma cells, triggers immune response
??
134
Canine Melanoma vaccine ONCEPT usage and dosing
USDA approved
Stage 2 or 3 melanoma in conjunction with standard tx for local disease
4 doses: 2 weeks apart + 6 month booster
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Efficacy of melanoma vaccine
Initially looked great, but more recent studies showed there were no differences in survival
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Melanoma vaccine-- adverse effects
Injection site pain, Fever, Hypersensitivity (rare), localized vitilligo
137
Metronomics- define
Lose doses, more frequently
| May have anti-angiogenic effects
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Metronomics-- tends to be ____ agents
alkylating agents, because oral
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Metronomic Lomustine study
discontinued due to toxicities (GI, Liver, azotemia, thrombocytopenia, neutropenia)
140
Metronomic cyclophosphamide toxicity??
Cystitis?
141
How to manage nausea/vomiting effects of chemo drugs
Maropitant
| Odansetron, Butorphanol (specific- PRIOR to cisplatin)
142
Drugs causing diarrhea
Doxorubicin most likely
Loperamide
Morphine
Metronidazole (esp if due to bacterial overgrowth)
143
What is imporatnt about Loperamide
must know MDR1 status!
144
How to prevent excess histamine effects from mast cell tumors
```
Prevent GI ulceration with H2 blockers (famotidine)
Use PPIs (omeprazole)
```
145
Managing neutropenia depends on what two things
Grade and Presence of fever
Can be grade 1-2, Grade 3-4, or Febrile
146
Grade 1-2 neutropenia
Afebrile
Oral antibacterial agent
Selection based on most likely source of infection
147
Grade 3-4
Afebrile
Oral antibacterial agent
4 quadrant coverage
148
Febrile stage
Parenteral
| 4 quadrant coverage
149
What can you give prior to treatment of a cytotoxic drug, that can cause prolonged neutropenia
rHG-CSF (h for Human recombinant-- they get AB, thus not used often)
Don't keep neutropenic patients in hospital too long!!!
150
Which drugs are substrates for P-gp
Vincristine and vinblastine
Doxorubicin
Paclitaxel
151
Which chemo drugs considered "natural products"
Vincristine and vinblastine
152
Dogs with MDR1 mutation (even heterozygotes) more likely to develop what
BM suppression (neutropenia, thrombocytopenia)
GI (vincristine!)
Neuropathy
153
Why do dogs with MDR1 mutation develop problems
P-gp mediated biliary excretion (Vincristine and vinblastine, doxorubicin, paxiltaxel)
154
Who to test for MDR1 mutation
ALL herding breeds, mixed breeds
| severe adverse affects!
155
What dose reduction (%) should be made for MDR1 mutant/mutant
50% decrease
156
What dose reduction (%) should be made for MDR1 mutant/normal
25%
157
Case example with MDR1- rhonda
see case
looks like Doxorubicin, Vinorelbine, Taxol (Paclitaxel) cause severe BM suppression
