cancer
imbalance in cell proliferation and cell death (apoptosis). Persistent proliferation of cells
that differentiate poorly or not at all. Rapid vs. slow growth. Lack contact inhibition! Able
to invade and destroy neighboring tissue. Capable of metastases.
metastases
when cancer cells that leave the primary tumor travel through lymphatic and blood
vessels and colonize distant sites. Poor prognosis in this case.
contact inhibition
property of cells in which when cells touch one another, it sends an autocrine signal to
stop reproducing. Cancer cells lack this, so when they touch each other, that signal isn't
sent and they keep growing and destroying tissue architecture.
cancer treatment
includes radiation and surgery. When neoplasms are disseminated and/or not amenable
to surgery, or as a supplement to surgery and radiation. Include conventional
chemotherapy, hormonal therapy, rationally designed therapy, immunotherapies and
prophylaxis, and combinations of above.
challenges of chemotherapy
include failure to detect disease early, 100% kill requirement (meaning multiple rounds
of treatment are needed), drug resistance, and narrow therapeutic index/toxic side
effects.
intrinsic drug resistance
challenge of chemotherapy. Loss/mutation of tumor suppressors. Include mutation/loss
of p53 which causes resistance to some chemotherapeutics. This is in 50% of tumors,
so common.
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acquired drug resistance
challenge of chemotherapy. Tumor responds to single drug initially, but over time
develops resistance. Multidrug resistance gene (MDR-1; P-glycoprotein) pumps many
drugs out of the cell. Cross resistance to more than one class of drug.
narrow therapeutic index/toxic side effects
challenge of chemotherapy. Includes bone marrow suppression (often dose limiting),
increased risk of infection, febrile neutropenia, mucositis throughout GI tract, nausea,
vomiting, cachexia, alopecia, damage to reproductive system, neurotoxicity, and DNA
damage (treatment can be mutagenic, carcinogenic, and teratogenic).
strategies to maximize efficacy and minimize side-effects
include combination therapy to reduce likelihood of resistance, rationally-designed
therapy tailored to patient's molecular abnormalities (i.e. CML, specific types of breast
cancer), optimization of dosing and route, intermittent therapy to allow normal cell
recovery (especially bone marrow), and supportive therapy (to allow patient to tolerate
medicine).
G1 phase
RNA and protein synthesis (40% of the time)
S phase
DNA synthesis (39% of the time)
G2 phase
tetraploid, prepare for mitosis. 19% of the time.
M phase
mitosis, diploid daughter cells. 2% of the time.
G0 phase
quiescent; differentiation or re-enter cell cycle.
chemotherapeutics
drugs to treat cancer. Work in any phase in the cell cycle to initiate cell death
(apoptosis).
cell cycle specific
chemotherapeutic drugs active only in specific cell cycle phases. Include inhibitors of
DNA synthesis (S phase) like antimetabolites and inhibitors of mitosis (M phase) like
microtubule inhibitors. Also include topoisomerase inhibitors (G2).
cell cycle nonspecific
chemotherapetuic drugs that target both resting and dividing cells. Include inhibitors of
gene expression/DNA damaging agents like alkylating agents, antibiotics,
estrogen/androgen antagonists.
protein synthesis
begins with purine and pyrimidine synthesis, which then is made into ribonucleotides,
then deoxyribonucleotides, then DNA, then RNA, then proteins.
antimetabolites
cell cycle specific; structural analogs of aendogenous molecules required for the
synthesis of DNA which interferes with DNA synthesis. S phase specific! Most effective
for rapidly proliferating tumors (and rapid DNA replication) like leukemias and
lymphomas. All cause myelosupression. These are folic acid mimics. But technically,
since only S phase, only targets 40% of tumor at any given time.
methrotrexate
type of antimetabolite. Primary toxic effects on rapidly dividing cells of bone marrow and
intestinal epithelium causing mucositis, myelosuppression, and thrombocytopenia. Can
have nephrotoxicity. Inflammatory response in CSF, not reversed by Leucovorin.
microtubule inhibitors
cell cycle specific inhibitors of mitosis and splitting of the microtubule spindles. Include
vinca alkaloids and taxanes. Have acquired resistance due to MDR-1 gene
unfortunately. Only 2% of cell cycle though, so not vastly sensitivity. Also target tubules
in neurons, so can be neurotoxic.
vinca alkaloids
microtubule inhibitors including vincristine and vinblastine. Vincristine is used to treat
pediatric leukemias with corticosteroids and solid tumors, adult lymphomas. Vinblastin is
used to treat testicular cancer (with bleomycin and cisplatin) and lymphomas*.
Neurotoxicity with vincristine but not as much with vinblastine.
taxanes
microtubule inhibitors that include paclitaxel and docetaxel. Cisplatin-resistant solid
tumors. Can cause peripheral neuropathy.
topoisomerase inhibitors
inhibits of the action of an enzyme* that is required for mitosis. Includes etoposide.
Potential development of resistance to MDR-1 gene (causes upregulation and tumor no
longer responds and becomes resistant).
MDR1 gene
a mutated gene that develops in response to some chemotherapeutics. This allows the
tumor cell to develop acquired resistance. For example, Taxane is administered and
goes into the tumor cell, the gene synthesizes a channel that pumps the Taxane back
out, eliminating its effect on intracellular drug targets and thus death. This gene is
usually good in non tumor cells as a way to prevent cell death from harmful chemicals,
but when developed in tumor cells, prevents chemotherapeutics from working. Can be
upregulated by Etoposide too.
DNA intercalating/damaging agents
cell cycle non specific chemotherapeutic. Intercalate into DNA and prevent transcription.
Cause DNA strands to break. Mainly includes antibiotics.
bleomycin
antibiotic and DNA intercalating/damaging agent that is used for squamous carcinomas
of the head, neck, and lungs (combo therapies with cisplatin and others). Curative for
germ cell tumors of the testis (with cisplatin/vinblastine or cisplatin/etoposide). Highly
effective for germ cell tumors of the ovary. Minimally myelo- and immunosuppressive.
Toxicity though - pulmonary fibrosis, cutaneous toxicity (hyperkeratosis, ulceration), and
rare fulminant reaction in lymphoma patients.
alkylating agents
cell cycle non specific (because DNA is always being expressed). Highly reactive
compounds that cause cross linking of DNA. Prevent gene expression; DNA damage
causes apoptosis. Dose limiting toxicity to bone marrow and intestinal mucosa. All are
mutagenic/carcinogenic (because effect on DNA) and can actually induce leukemia.
Cells mutant for p53 have intrinsic resistance against these drugs! Include nitrogen
mustards, platinum compounds, nitrosoureas, alkyl sulfonates.
nitrogen mustards
alkylating agents (DNA damage). Relatives of WW1 mustard gases. Includes
cyclophosphamide. Very broad spectrum - highly effective against Burkitt's lymphoma.
Adjuvant therapy after surgery for breast cancer. Potent immunosuppression, GI
ulceration, hemorrhagic cystitis, marked alopecia, nausea and vomiting.
platinum compounds
alkylating agents; include cisplatin and carboplatin. Cisplatin (with bleomycin, etoposide,
and vinblastine) for testicular cancer (85% cure). Carboplastin (with paclitaxel or
cyclophosphamide) for ovarian cancer. Nephrotoxicity (minimized with hydration and
diuresis), ototoxicity, severe nausea and vomiting.
p53
tumor suppressor gene. This can be mutated in cancer cells. Usually alkylating agents
will cause damage to the DNA, which will activate this and cause cell death. But
mutations will cause this p53 to be inactivated in some way and instead when
chemotherapeutics attempt to active p53, nothing happens and there is resistance to
therapy.
rationally designed therapy
includes drugs targeted to be causative molecular abnormality; becoming more
common. Include imatinib (Gleevec). This is an inhibitor of bcr-abl tyrosine kinase
causative for, and found only in, chronic myelocytic leukemia (+ some ALL). Remarkably
effective with few side effects. Low incidence of resistance. Mutations in bcr-abl causing
resistance can be identified and drug structure can be modified to overcome resistance.
hormonal agents
breast and prostat tumors frequently require estrogen/androgen for growth/survival so
these will block the synthesis of those. Tumor cell growth/survival can be inhibited by
lowering hormone levels of antagonizing hormone function. Relatively minor side effects
with no myelosuppression or mucositis.
antiestrogens
first choice for hormonal therapy of estrogon therapy (ER+ breast cancer). Tamoxifen
approved for breast cancer prevention in women at high risk (age, history, heredity).
Raloxifene, a drug used to treat osteoporosis, was found to dramatically reduce risk of
invasive breast cancer. Inhibit binding of estradiol to the ER and subsequent gene
transcription (less effective in premenopausal women due to high circulating estrogen;
ineffective in ER negative tumors). Toxicity - concerns for endometrial cancer.
anti-androgens
useful in the treatment of prostate cancer. Include steroidal like cyproterone that inhibit
androgen binding to the AR and non-steroidal like bicalutamide that inhibit nuclear
translocation to the AR. These inhibit AR-dependent gene transcription. Relatively minor
toxicity.
immunotherapy
programmed cell death protein therapies that allow immune system to tackle the tumor.
Antibodies to PD-1 (Nivolumab and Pembrolizumab) allow T cells to attack tumors that
otherwise would suppress T cell activity. Melanomas upregulate expression of PDL and
become invisible to T cells so this would help to prevent that.
rituximab
humanized monoclonal antibodies used for immunotherapy treatment for cancer. Binds
to CD20 (surface antigen) found on 90% of non-Hodgkin's lymphomas. Sometimes
conjugated with radioactive iodine. For relapsed/refractory B cell non Hodgkin's
lymphomas. May cause tumor lysis syndrome.
trastuzumab (Herceptin)
antibody to human epidermal growth factor receptor 2 (HER2). Approved for treatment
(in combo with paclitaxel or doxorubicin) or metastatic breast cancers over expression
HER2. Side effect may be hypersensitivity.
tumor lysis syndrome
can be caused via rituximab. The drug can be so effective and bring about so much
tumor cell death that al the debris form the cell lysis can cause acute kidney failure.
prophylaxis
include vaccines against HPV. These elicit humoral immune response to select HPVs.
Include quadrivalent (HPV 6, 11, 16, 18), divalent (HPV 16, 18), nonavalent (all types
above). For males and females. Routine screening and intervention is still current
standard for care for cervical cancer. Vaccines do not protect against other causes of
cervical/anal cancer or do not protect against viruses person already has. Do not treat
existing cervical/anal cancer.
MOPP regiment
for Hodgkin's disease. Include Mechlorethiamine, oncovin (Vincristine), procarbazine,
and prednisone.
CMF regimen
for breast cancer; include cyclophosphamide, methotrexate, fluorouracil.
ABVD regiment
for Hodgkin's. Include adriamycin, bleomycin, vinblastine, and decarbazine.
filgrastim
support therapy; granulocyte colony-stimulating factor, prophylaxis of chemotherapy-
induced neutropenia.
sargramostim
support therapy; granulocte/macrophage colony-stimulating factor, aids neutrophil
recovery in AML patients.
pamidronate
support therapy; prevents hypercalcemia and bone resorption associated with
malignancy.
erythropoietin and darbopoiten
support therapy; stimulates bone marrow RBC production, treats anemia resulting from
myelosuppressive therapy.
leucovorin
support therapy; folate supplement.
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