PHRM 4180 Final Exam: Anti-Tumor Antibiotics

Anti-tumor antibiotics derived from:

Streptomyces species

How do anti-tumor antibiotics work?

They interact with DNA, generally through intercalation or insertion between DNA base pairs

This interaction either inhibits the enzymes of DNA and/or RNA synthesis or induces strand breaks in DNA

Bleomycin

Mixture of Bleomycin A2 and B2 as a copper chelate

Bleomycin is chemically considered:

A glycopeptide

Bleomycin can be divided into two regions; what are they?

Metal binding (pyrimidine) region

DNA binding (dithiazole) region

Metal binding region forms complexes with:

Divalent metals such as Fe++ and Cu++

Regions pictured

Bleomycin MOA

Dithiazole region intercalates into DNA and Fe is chelated by metal binding region

In presence of O2, iron is oxidized and the oxygen is reduced generating superoxide and hydroxyl radical, 2 ROS that cause DNA strand breaks

Bleomycin routes

IV and instillation into the bladder

Distribution of Bleomycin

Relatively high concentration seen in skin and lung after IV admin

Bleomycin uses

Ovarian cancer

Testicular cancer

Squamous cell carcinomas

Hodgkin's and non-Hodgkin's lymphoma

Bleomycin ADRs

Pigmentation of the skin and nail beds

Erythema and ulceration of elbows, knuckles, and other pressure points (cell memory)

Pulmonary toxicity (DL)

Little BMS

NV

Headache

Pulmonary toxicity

Begins with dry cough, fine rales, infiltrates on CXR

May progress to pulmonary fibrosis

Bleomycin sensitizes what?

Tumor and normal tissue sensitized to radiation

Actinomycin D structure

Composed of a planar (phenoxazone) ring system and two flexible cyclic peptides

Actinomycin D MOA

Planar ring system intercalated between G-C base pairs of DNA, where G is on opposite strands

Cyclic peptides extend into minor groove

End result of MOA

Transcription of DNA by DNA dependent RNA polymerase is inhibited

Actinomycin D secondary MOA

Also causes single strand breaks in DNA either by free radical generation or by inhibition of topoisomerase II

Actinomycin D route

IV

Actinomycin D uses

Testicular cancer

Sarcomas

Wilm's tumor

Actinomycin D ADRs

NV (pre-medicate to avoid)

BMS (DL)

Sore throat and mouth ulcers common

Actinomycin dose adjustment

Reduce dose in renal and hepatic impairment

Anthracyclines structure

Tetracyclic planar ring system

Quinone and hydroquinone next to each other allow compounds to function as EDG/EWGs

Anthracyclines MOA

Planar ring structure intercalates into DNA, unlike Actinomycin D there is no base pair preference

Sugar portion of Anthracyclines located where?

Minor groove

MOA interaction causes:

Inhibition of topo II's breakage reaction, which leads to DNA strand breaks, not totally known

Anthracyclines may also chelate:

Iron, and iron chelate can form complex with DNA to generate free radicals

Iron chelation MOA place in therapy

Mechanism probably minor in overall cytotoxicity

Con of drug/Fe complex

Primary reason cardiotoxicity is associated with anthracyclines

Two types of cardiotoxic changes seen with anthracyclines

Early transient ECG changes

Delayed progressive cardiomyopathy

Early cardiotoxic changes seen

Characterized by tachycardia, extra-systolic contractions and ST-T wave alterations

Duration of cardiotoxic ADRs

Arrhythmias reverse in hours

ST-T wave changes in a few weeks

Long-term cardiomyopathy manifests as:

Severe rapidly progressing CHF

Doxorubicin total cumulative life dose

>550 mg/m^2

Daunorubicin total cumulative life dose

>900 mg/m^2

Epirubicin total cumulative life dose

>900 mg/m^2

Dexrazoxane MOA

EDTA derivative that effectively competes for iron with anthracyclines, reducing incidences of CHF and increasing total cumulative dose allowed

Dexrazoxane indicated for:

Patients who have received 300 mg/m^2 of doxorubicin and who need to receive additional therapy

Dexrazoxane ADR

Increased BMS

Dexrazoxane dosing

Dosage 10:1 Zinecard:Doxorubicin

Doxorubicin uses

Wide range of tumors

Breast, lung, ovarian, thyroid, GI

Usually used in combo

Doxorubicin ADRs

CHF (DL)

Red discoloration of urine

Sensitization of normal and tumor tissue to radiation

Red/peeling skin

Daunorubicin uses

Primarily acute leukemia

Daunorubicin ADRs

CHF (DL)

Red urine

Mouth ulcers

Alopecia

Recall reaction

Epirubicin structure

Structurally similar to doxorubicin but sugar OH is up instead of down

Epirubicin uses

Breast cancer (combo)

CHF in Epirubicin

Low incidence of CHF if <550 mg/m^2 cumulative dose

Idarubicin uses

Acute leukemia

Idarubicin total cumulative lifetime dose

150 mg/m^2

Idarubicin issue

Metabolite has 55h half-life and is cardiotoxic

Valrubicin is different because

No IV use, instillation into bladder for those who have failed primary therapy for bladder carcinoma

Valrubicin ADRs

Red urine 24h after instillation

Mitoxantrone

Anthracycline analog (synthetic)

What makes mitoxantrone effect different?

Reduced free radical production (less cardiotoxic, less NV)

Mitoxantrone MOA

Intercalates into DNA and causes DNA strand breaks by inhibiting Topo II

Mitoxantrone uses

Breast cancer

Leukemias

Lymphomas

Mitoxantrone ADRs

BMS (DL)

Mouth ulcers

Blue discoloration of urine, fingernails, whites of eyes, and around inj site

Pilcamycin has high affinity for:

Ca++ and Mg++

Pilcamycin MOA

Intercalates into DNA with a preference for GC base pairs

Interferes with RNA synthesis

Plicamycin uses

Primarily for hypercalcemia

Testicular cancer (rare)

Plicamycin ADRs

Thrombocytopenia (BMS)

Bleeding disorders due to decreased Ca

Mouth ulcers

CNS depression

Mitomycin

Antibiotic but an alkylating agent

Note aziridine ring

Mitomycin MOA

Bifunctional alkylating agents causing cross linking of DNA

Inducing single strand breaks in DNA

Mitomycin uses

Stomach cancers

Pancreatic cancers

In combo for variety of other cancers

Mitomycin ADRs

BMS (DL)

Pulmonary fibrosis

Recall reaction