MG - infectious diseases and oncology 8

Cancer medications

invasion

cancer cells grow into surrounding tissues and blood vessels

metastatis

cancer cells are transported by the circulatory system to distant sites

benign tumors

not cancer, these cells grow only locally and cannot spread by invasion or metastatis. these can crowd out the surrounding cells

malignant tumors

cancer, cells invade neighboring tissues, enter blood vessels and metastatise to different sites.

can cause secondary tumors and block blood vesselsTNM

TNM classification

t = size of tumor

n = nearby / regional lymph nodes that are involved

M = distant metastasis

carcinomas

solid tumors

lung, breast, colon, bladder, prostate

sarcomas

solid tumors

fat, bone, muscle

liquid tumors

leukemias(bloodstream)

lymphomas(lymph nodes)

carcinogens

ionising radiation, chemicals, virus infection, hereditary predisposition

p53 tumor suppressor gene

normally this initiates self-destruction, but in mutated cancer cells it does not anymore

therapy for cancer

local: surgery / radiation

systemic:

• primary chemotherapy: administered as primary treatment there is no alternative

• neoadjuvant chemotherapy: localized cancer, alternatives exists but less effective.

  • adjuvant chemo: chemo is administered after surgery

cytotoxic agents

direct damage to cancer cells > apoptosis

decrease in tumor size

intermittent treatment schedule

• possible because of long lasting effect

• needed because of the side effects

toxic effects

• mostly bone marrow and GI damaging effects

alkylating agents

MOA: cytotoxic effects due to alkylation of DNA within the nucleus

resistance: increased capability to repair DNA lesions

• decreased transport of the alkylating drug into the cell

• increased expression or activity of glutathione and -associated proteins

SE: generally dose-related and in rapidly growing tissues, nausea, vomiting, potent vesicants, cause secondary malignancies

cyclophosphamide, ifosfamide

alkylating agents(bis(chloroethyl)amines) > cytotoxic

indication: solid tumors, lymphomas, leukemias, immune suppression

toxicity: decrease in bone marrow, vomiting, alopecia, neurotoxicity, hemorrhagic cystitis(mesna)

estramustin

alkylating agent(bis(chloroethyl)amines) > cytotoxic

MOA: alkylating agent + estrogen

toxicity: estrogen effects

indication: prostate cancer

carmustine

alkylating agent (nitrosoureas) > cytotoxic

toxicity: bone marrow, strong emetogenic

indication: brain tumors

temozolomide

alkylating agent > cytotoxic

oral chemotherapy

toxicity: bone marrow, vomiting, genotoxic, teratogenic, fetotoxic

cisplatin, carboplatin, oxaliplatin

alkylating agents(platinum analogues) > cytotoxic

MOA: alkylating, inhibition of DNA synthesis and function

toxicity: strong emetic effect(cisplatin), kidney damage/hearing damage(cisplatin), neurotoxicity(cisplatin/oxaliplatin), bone marrow(carboplatin)

indications: solid tumors, colorectal cancer(oxaliplatin)

methotrexate

antimetabolite (anti-folate) > cytotoxic

MOA: binds to active catalytic site of DHF reductase resulting in the inhibition of the THF synthesis, stopping the de novo synthesis of thymidylate, purine nucleotides and the amino acids serine and methionine.

indications: acute lympohoid leukemia, non-Hodkin lymphoma, various solid tumors

resistance:

• reduced transport

• decreased formation of cytotoxic MTX polyglulatmates

• increased levels of the target enzyme through gene amplification

• reduced affinity

• MDR transporter activation

PK: mainly renal(IA: aspirin, NSAIDs, penicillin, cephalosporines)

SE/toxicity: mucositis, GI, liver and kidney toxicity, hair loss, bone marrow toxicity

5-fluorouracil

antimetabolite - fluoropyrimidines > cytotoxic

MOA: requires activation with enzymatic reactions

• inhibits the DNA synthesis

• FUTP gets incoorporated into the RNA and FdUTP into the cellular DNA resulting in a decreased function and synthesis

PK: iv, schedule-dependent activity

• DPD deficiency!!!!

SE: mucositis/stomatitis, hand-foot syndrome, myelo suppression

indication

• colorectal cancer

  • wide variety of solid tumors

capecitabine

the prodrug of 5-FU > cytotoxic

indications: metastatic breast cancer

• stage III and high-risk stage II colon cancer

• metastatic colorectal cancer

6-mercaptopurine, 6-thioguanine

purine antagonists - anti-metabolites > cytotoxic

MOA: metabolized and then inhibits several enzymes of the de novo purine nucleotide synthesis

• can be incorporated in both the DNA and RNA

SE: myelotoxicity, GI effects, anorexia

indication: childhood acute leukemia

for resistant cases: nelarabine

hydroxycarbamide (hydroxyurea)

antimetabolite > cytotoxic

MOA: inhibits the diphosphate reductase inhibiting the conversion of ribonucleotides to deoxyribonucleotides

toxicity: myelo suppression

SE: drowsiness, nausea, vomiting, constipation, mucositis, anorexia, stomatitis, alopecia, abnormal liver enzymes, creatine and blood urea nitrogen

indication: chronic myelogenous leukemia, polycythaemia vera

topoisomerase

I = cuts one strand

II = cuts two strands

plays a key role in DNA repair

irinotecan, topotecan

topoisomerase I inhibitor > cytotoxic

MOA: activated by hydrolysis, inhibition of topoisomerase I resulting in the inhibition of transcription and replication inhibition, DNA break, resulting in an increase is p53 resulting in apoptosis

• there is effect during the whole cell cycle

• resistance can occur due to the multidrug resistance transporter

SE: cholinergic syndrome, diarrhea, vomiting, bone marrow suppression

indication: colon cancer

doxorubicin, daunorubicin, epirubicin

antracyclines > topoisomerase II inhibitors > cytotoxic

MOA: topoisomerase II inhibitor resulting in DNA double strand breaks and the intercalation into the DNA

SE/toxicity:

• cardiotoxicity, both acute and delayed

• myelotoxicity

• GI

indications: most widely used

• doxorubicin: various solid tumors and hematologic malignancies

• daunorubicin: hematologic malignancies. this is a mutagen and teratogen, which is dangerous for the personnel

etoposide

podophyllins > topoisomerase II inhibitor > cytotoxic

MOA: apoptosis induction due to double strand breaks

indications: some solid tumors and hematologic tumors

vincristin, vinblastin, vinorelbin

vinca alkaloids > anti-microtubule drugs > cytotoxic

MOA: inhibition of the tubulin polymerixation, disrupting the assembly of microtubules stopping the cell division

PK: metabolized by the liver(CYP450) and excreted via the hepatobiliary system

SE: vomiting, neurotoxicity(vincristin), potent vesicant, bone marrow suppression, alopecia, hyperurikemia

indications: acute lymphoblastic leukemia and lymphomas and some solid tumors

paclitaxel, docetaxel, cabazitaxel

taxanes > anti-microtubule drugs > cytotoxic

MOA: high affinity binding to the microtubules increasing the polymerization inhibiting the mitosis and cell division

PK: metabolized by CYP, excreted via the hepatobiliary route

SE: acute hypersensitive reactions(paclitaxel) > preventitive anti-histamine and steroid treatment

• hypersensitivity, myelotoxicity, cardiotoxicity, neuropathy and liver toxicity

• neutropenia(docetaxel)

indications: solid tumors in a broad range

medroxyprogesterone-acetate(MPA), megestrol

hormone and their derivative > cytostatic

MOA: decrease the LH and FSH hormone resulting in disturbance in the RNA and DNA synthesis in the estradiol dependent cells

might be used in cases of endometrium-carcinoma and metastasizing breast cancer

tamoxifen, clomifene, fulvestrant

anti-estrogens > hormones and their derivatives > cytostatic

MOA: competitive inhibitors of estrogen

indication: adjuvant treatment of breast cancer after surgery

SE: hot flushes, thromboemobolism, danger of endometrial cancer, pruritus vulvae, nausea, headaches, edema, thrombocytopenia

enastrozol, letrozol, exemestan

aromatase inhibitors > hormones and their derivatives > cytostatic

MOA: inhibit the transforming of testosterone to estrogen

indication: tamoxifen-resistant breast cancer

SE: arthralgia, bone pain, fatigue, headaches, hot flushes, alopecia

goserelin, buserelin, leuproeline

GnRH agonist > hormones and their derivatives > cytostatic

MOA: analogues with an extended duration of activity, after chronic administration there is sustained suppression of LH and FSH

indication: prostate cancer, late-stage breast cancer

SE: decrease in libido, hot flushes, headaches, diarrhea, increase in serom testosterone(might cause impotence), bone metastases

degarelix

GnRH antagonist > hormones and their derivatives > cytostatic

MOA: reversibly binds to the GnRH receptors decreasing LH and FSH decreasing testosterone levels

indication: advanced prostate cancer

SE: injection site reactions, increased serum transaminases, hot flushes, weight change, fatigue

bicalutamide, apalutamide

anti-androgens > hormones and their derivatives > cytostatic

MOA: androgen receptor inhibitor preventing testosterone from stimulating cell growth

indication: prostate cancer

SE: GI, pressure sensitivity nipples

cortison, hydrocortison, prednisolon, methylprednisolon, betamethason, dexamethason, triamcinolon

glucocorticosteroids > hormones and their derivatives > cytostatic

MOA: pain alleviation, inhibition of inflammation, inhibition of estradiol release and formation

SE: osteoporosis, euphoria/depression, hyperglycemia, increased risk of infections, skin thinning, cushingoid appearance, elevated intraocular pressure/glaucoma, fluid retention, hypertension, gastritis, peptic ulcers

bleomycin

cytostatic antibiotic

MOA: small peptide that contains DNA-binding region and iron-binding domain. toxicity via free radical formation resulting in the inhibition of the DNA biosynthesis

SE/toxicity: pulmonary toxicity - pneumonitis with cough, dyspnea, dry respiratory crackels on physical examination

PK: excreted mainly via the kidney

indications: (non)-Hodgkin’s lymphomas, germ cell tumor, head and neck cancer, squamous cell cancer of the skin, cervix and vulva

interferon a

interferon > cytokines > cytostatic

antiviral, antiproliferative, immune modulatory effects

• activation of transcription factors

indications: various diseases and conditions

SE: flu-like symptoms, anorexia, drowsiness, myelosuppression, kidney- and cardiotoxicity, autoimmune reactions, psychosis

aldesleukin

interleukins > cytokines > cytostatic

MOA: promotes proliferation, differentiation and recruitment of B and T cells, NK cells and thymocytes

indication: metastatic renal cell carcinoma

side effects: fever, chills, flu-like, angina pectoris, decrease in BP, arrythmia, GI, respiratory, neuronal disturbances

cancer immunoediting

I > elimination phase

• characterized by T, B and NK cell effector function

• mediated by cytokines

II > equilibrium phase

• balance between immune mediated destruction and persistence of rare malignant clones

III > immunologic escape

• malignant clones have acquired the ability to evade the adaptive immune system resulting in the loss or alteration of specific antigens or antigenic machinery

ErbB family proteins

receptor tyrosine kinases

• EGFR overexpression: many cancers

  • ErbB2 overexpression: breast, ovarian, bladder, non-small cell lung carcinoma as well as several other tumor types

gefitinib, erlotinib, afatinib

HER1/EGFR inhibitors > cancer immunotherapy

effective only in the case of EGFR receptor mutation then there is inhibition of tumor angiogenesis

indication: non-small cell lung cancer

SE: skin rashes, diarrhea, transanimase elevation

lapatinib

HER1/EGFR and HER2/neu inhibitor > cancer immunotherapy

indication: HER+ breast cancer

SE: cardiotoxic, GI

sunitinib

C-kit and PDGFR inhibitor > cancer immunotherapy

• also inhibits VEGFR

indication: kidney, GI tumors, neuroendocrine pancreas

SE: high bp, fatigue, diarrhea, nausea, anorexia, yellow skin discoloration, hand-foot skin reaction, stomatitis

anti-angiogenic therapy of cancer

rate-limiting step for numerous pathologic processes including cancer growth

sorafenib

multitargeted tyrosine kinase inhibitor > cancer immunotherapy

• inhibits the VEGFR-2, FLT3, PDGFR and FGFR

• indicated in kidney, liver and pancreas carcinomas

sunitinib

multitargeted tyrosine kinase inhibitor > cancer immunotherapy

kdieny, GI stromal tumor, neuroendocrine pancreas tumor

imatinib

non-receptor tyrosine kinase > cancer immunotherapy

• specific gene abnormality in leukemia cells (BCR-ABL1)

MOA: disrupts the ATP phosphate binding site to block the catalytic activity of the enzyme

indications: philadelphia chromosome positive chronic myeloid leukemia and positive acute lymphoblastic leukemia

SE: fluid retention, GI bleeding, bone marrow suppression, liver problems, heart failure, common(GI, muscle pain, headache, rash)

aflibercept

fusion protein against VEGF > cancer immunotherapy

soluble decoy receptor

indication: colorectal cancer

SE: systemic (hypertension, CNS, GI, reduced blood cell count)

everolimus

mTOR inhibitor > cancer immunotherapy

MOA: halting the cell cycle in the G1 phase

indicated: HER2 - breast cancer, advanced/metastatic/unresectable progressive neuroendocrine tumors

• liver and renal transplantation

cetuximab

EGFR antibodies > monoclonal antibodies

MOA: binds specifically to the epidermal growth factor receptor cells

indication: metastatic colorectal cancer and squamous cell cancer of the head and neck

SE: allergy!!, fatigue, malaise, pain, peripheral sensory neuropathy, dermatologic symptoms, GI, myelosuppression

trastuzumab

HER2 antibodies > monoclonal antibodies

MOA: binds to the extracellular domain of HER2

indication: HER2 overexpressing metatstatic breast cancer

• HER2 overexpressing metastatic gastric of gastroesophageal junction adenocarcinoma

SE: cardiac failure

• allergy!!!

• in women > contraception during and for at least 6 months afterwards

• CNS/GI disturbances

• skin rash

• flu like symptoms

bevacizumab

VEGF-A antibody > monoclonal antibody

MOA: binds to and neutralizes VEGF

indication:

• persistant/recurrent/metastatic cervical cancer

• first or second line treatmetn of metastatic colorectal cancer

• recurrent glioblastoma

• non-small cell lung cancer

• epithelial ovarian/fallopian tube/primary peritoneal cancer

• metastatic renal cell carcinoma

SE: common side effects

• GI perforations

• wound healing and surgical complications

• lowered blood cell count

rituximab

anti CD20-antibody > monoclonal antibodies

MOA: destroys both normal and malignant B-cells containing CD20 on the surface resulting in a new population of healthy B-cells developing from lymphoid stem cells

indication: CD20 positive CLL, NHL, PGA, RA, MPA

SE: serious including fatal reactions

• Hep B reactivation

• progressive multifocal leukoencephalopathy