Anti-neoplastic Drugs Part 1

How does cancer develop and how can it be described?

It develops from activation of oncogenes and loss of tumor suppressor function, and is characterized by uncontrolled cell growth.

which phase of the cell cycle is always on/dominant in cancer cells?

S phase

what is the goal of chemotherapy?

kill cancer cells without killing the patient

what repair mechanism is used to repair dimers?

nucleotide excision

3 types of single strand repair mechanisms

base excision

mismatch repair

nucleotide excision

2 types of double stranded DNA repair

non-homologous end joining

homologous recombination

what is cellular suicide provoked by?

DNA damage

What is the Harbor Process

N2 and H2 gases could be used to make NH3, a fertilizer

main cause of death from mustard gas

anemia resulting in white blood cell loss

half life of alkylating agents

1-3 hours

major toxicities of alkylating agents

nausea, immune suppression, mucositis

describe the mechanism of alkylating agents

nucleophilic substitution forms a cyclic sulfonium ion. This intermediate reaction cause permanent alkylation of the guanine nucleotide in DNA strands.

5 common alkylating agents

mechlorethamine

melphalan

chlorambucil

cyclophosphamide

ifosamide

main anti-folate to know

methotrexate

describe the mechanism of methotrexate

inhibits enzymes for nucleotide synthesis (purine and thymidine) like thymidylate synthase and dihydrofolate reductase

toxicity of methotrexate

Myelosuppression, mucositis/stomatitis/ulceration, nausea and vomiting, pulmonary fibrosis, nephrotoxicity

drug interactions of methotrexate

interferes with penicillin absorption, penicillin can reduce clearance of MTX leading to enhanced toxicity

pyrimidine analogs to know

5 Fu

Gemcitabine

Capecitabine

Cytarabine

describe the mechanism of pyrimidine analogues

disrupt DNA formation via incorporation into the strand

toxicity of 5-Fu

Myelosuppression, nausea and vomiting, hepatotoxicity, immunosuppression. Mucositis depends on administration route.

describe the mechanism of topoisomerase inhibitors

bind topoisomerase to prevent DNA replication leading to cell death

what does etoposide target and what are its toxicities?

TOPO II

myelosuppression, nausea

what do campothecins target and what is there toxicity?

TOPO I, myelosuppression and nausea

Mechanism of platinum drugs (cisplatin)

reacts with the N(7) of guanine to form adduct, which disrupt DNA structure and replication

3 cisplatins to know

cisplatin

oxaloplatin

carboplatin

uses of cisplatin and toxicity

Carcinoma of testis, prostate, cervix, ovary, endometrium, lung, bladder, head and neck; sarcoma; neuroblastoma

Toxicity: Nephrotoxicity, ototoxicity, nausea and vomiting, GI enterotoxicity, neurotoxicity, acute allergic reactions.

use and toxicity of oxaloplatin

Colorectal.

Toxicity: Pharyngolaryngeal dysesthesia (breathing swallowing diffulties), paresthesias(tingling), peripheral neuropathy, diarrhea, myelosuppression.

use and toxicity of carboplatin

Testicular and ovarian carcinoma, head and neck cancers, lung cancer

Toxicity: Myelosuppression, GI enterotoxicity, neurotoxicity

mechanism of anthracyclins (cytotoxic antibiotics)

intercalates with DNA causing topoisomerase stalling

3 anthracyclins to know

doxorubicin

dactinomycin

bleomycin

toxicity of doxorubicin

Myelosuppression, cardiotoxicity, GI enterotoxicity, alopecia, tissue Necrosis.

Almost all patients exhibit soreness of the mouth and develop mouth ulcers

toxicity of dactinomycin

Myelosuppression, GI enterotoxicity, dermatotoxicity, tissue necrosis, Mucositis

mechanism of bleomycin

Chelates Fe, which interacts w/ O2 → Generation of superoxide and/or hydroxyl radicals. Radicals degrade DNA → fragmentation, release of free bases.

2 DNA demethylating agents to know

azacytidine

decitabine

cell division requires coordinated dynamic _____ mediated events and DNA synthesis

microtubule

mechanism of taxanes

bind tubulin and prevent microtubule depolymerization

two taxanes to know and what are some toxicities associated with both?

paclitaxel and docetaxel

myelosuppression, hypersensitivity reaction, neuropathy

function of vinca alkaloids

binds tubulin and prevents microtubule polymerization

3 vinca alkaloids to know

vincristine, vinblastine, vinorelbine

mechanism of retinoic acid

prevents cell differentiation

2 possible adverse effects of retinoic acid

tooth enamel deposition

skin irritation

mechanism of bisphosphonates

mimic pyrophosphate's structure, thereby inhibiting activation of enzymes that utilize pyrophosphate

2 classes of bisphonates

N-containing bisphosphonates and non-N-containing bisphonates

What are N-bisphosphonates used to treat, and how long do they last in the body?

They are used to treat metastatic breast cancer and multiple myeloma, and they have a half-life of years.

dental side effect of bisphosphonates

osteonecrosis of the jaw