Vinca Alkaloids, Taxanes, Epipodophyllotoxins, Camptothecins, Hormones, Anti-hormones, Asparaginase, Monoclonal Antibodies and Cytokines

Vinca Alkaloids

Mitotic spindle poisons.

Vincristine is obtained from Vinca rosea

Mechanism of Action

– dimeric form, bind tubulin to form tubulin complex

– inhibit polymerization required for formation of microtubules

– mitotic arrest in metaphase, cell are not able to divide

Uses

1. Hematological – ALL / lymphoma / Multiple myloma

2. Pediatric – Wilm’s tumor, Ewing’s sarcoma, neuroblastoma

Toxicity

1. Neurotoxicity – per. sens neuropathy, CN palsies, ataxia,  seizures, coma

2. ANS dysfunction

3. SIADH

Image courtesy of CDC/Amanda Mills

Vinblastine

Source & Mechanism of Action – as vincristine

Toxicity

• Nausea
• Vomiting
• Alopecia
• Myelosuppression
• Potent vesicant, thrombophlebitis at site of administration

Uses

1.      Breast,
2.      Germ cell,
3.      Lymphomas

Vinorelabine

Semisynthetic compound

Mechanism of Action – as vincristine

Toxicity 

a.      Nausea
b.      Vomiting
c.       Myelosuppression
d.      Neurotoxicity
e.       SIADH
f.        Elevated LFTs

Uses

• Non Small Cell Lung cancer,
• Breast cancer

Taxanes

Paclitaxel

Obtained from Taxus brevifolia & T. baccata

Mechanism of Action

• Enhances tubulin polymerization
• Mitotic spindle poison

Microtubules formed are not stable structurally, in absence of tubulin associated proteins, CTP leads to disruption, so known as mitotic spindle poisons.

Uses

Solid tumors ( breast, lung, ovarian, prostate, head/neck, esophagus, bladder, Kaposi’s sarcoma )

Toxicity – hypersensitivity – treated by premedication (H2 blockers, dextramethasone)

– albumin-bound (abraxane) is having no hypersensitivity

Docetaxel

It is a semisynthetic derivative of Paclitaxel

Epipodophyllotoxins

Etoposide & Teniposide

Podophyllotoxin – semisynthetic derivative.

Mechanism of Action

• Inhibit topoisomerase II, uncoiling is inhibited, leading to DNA brakes
• DNA-drug-enzyme – complex is formed, drug acts by binding both DNA and enymes

Uses

• lymphoma
• gastric
• lung
• germ cell

Camptothecins

Topotecan & Irinotecan (prodrug)

• Obtained from Camptotheca acuminata
• Topotecan is prodrug, active metabolite is 1000 times active than parent compound.

Mechanism of Action – inhibit topoisomerase I, interfering with DNA replication

Uses – metastatic colorectal Carcinoma

Adverse Drug Reactions –Myelosuppression / Diarrhea (acute & chronic)

Giving atropine effectively treats diarrhea. Chronic diarrhea appears 2-10 days after treatment.

Hormones & Anti-hormones

• Glucocorticoids
• Estrogen
• Progestins
• Androgens

Antihormones

a. Anti-estrogen – Tamoxifen
–used in breast Cancer
b. Anti-androgen – Flutamide
–used in prostate Cancer
GnRH agonist – Goserelin / Leuprolide
– transient release of FSH / LH, pulsatile nature is suppressed, effective in releasing sex hormones, estrogen and progesterone

– used in prostate Cancer

d. GnRH antagonist   – Abarelix

e. Aromatase inhibitor  – Anastrozole

                                               – Aminoglutethimide

– inhibit conversion of androgen to estrogen in fatty tissues of body

– used in prostate / breast Cancer

Asparaginase

Enzyme – produced by bacterial culture e.g. E. coli

Mechanism of Action

Normally L-asparagine present in blood is taken up by malignant cells and used to synthesize proteins, as have no asparagine synthase so rely on external source.

On other hand, normal cells have enzyme for own protein synthesis, when asparaginase enzyme is given, it degrades it into aspartic acid and ammonia, thus malignant cells are unable to produce it.

– Lack of asparagine synthetase – inhibits protein synthesis

Toxicity

– Hypersensitivity

–  Neurotoxicity

–  Pancreatitis

–  Altered clotting factors

Uses –  ALL (childhood)

Retinoic acid derivatives

Tretinoin

Used in APL

Mechanism of Action-Induction of terminal differentiation of promyelocytes.

Toxicity

Very typical toxicity profile.

Vit A toxicity
a.      Dry skin, mucous membranes
b.      Pruritis
c.       Conjunctivitis
d.      fever

Retinoic acid syndrome

Manifests as:

a.      Fever
b.      Leukocytosis
c.       Weight gain
d.      Pleural and pericardial effusion
e.       Pulmonary infiltrate
f.        Dyspnea

Hyperlipidemias

a.      Increased cholesterol
b.      Increased TGs
CNS 
a.      Dizziness
b.      Anxiety
c.       Agitation
d.      Depression
e.       Confusion

GIT / Hepatic
a.      Abdominal pain
b.      Diarrhea

c.       Transient increase in LFTs

Monoclonal antibodies

Monoclonal antibodies are the molecules formed against antigen. They are produced by single B-cell line, so called so. They are highly specific towards single type of antigen, so toxic effects are limited because of high specificity.

Production

Antigen of interest is injected into animal e.g. mice, whose immunity is stimulated. B cells against antigen start forming antibodies, which are quantitively very less thus cannot be used clinically. These stimulated B cells are removed and are fused with myeloma tumor cells. Myeloma is a B cell cancer having lost the capacity to form antibodies but having rapid replication or growth rate.

• Hybridoma – B-cell + Myeloma tumor cell

Once fused, B cells also replicate, thus lots of antibodies are produced. Either germ tissue culture is obtained or injected back into animal where grow and give rise to lots of antibodies. Not used because of ethical issues.               

Chimeric antibodies may produce hypersensitivity reactions where administered to humans. Humanized by removing major portion of animal origin and replacing it with antibody portion:

1. Constant portion human origin
2. Antigenic variable portion of animal source.

There are many examples:

• Rituximab – anti CD20 on B lymphocytes

                                    –used in Non Hodgkin’s lymphoma

• Trastuzumab – anti EGFR receptor (epidermal growth factor receptor) – HER-2/neu

                                         –used in metastatic breast Cancer

• Bevacizumab – anti-VEGF-A

                                       –used in metastatic colorectal Cancer

Cytokines

Small protein molecules/peptides normally present in body.

Interferons

• Three forms: Alpha / beta / gamma
• Alpha form is in clinical use.

Mechanism of Action – mainly immunomodulatory

• When immunity is depressed, they enhance it.
• When overexpressed, suppress it.
• Act as Antiproliferative

Uses – IFN-α  –

1.      CML
2.      hairy cell leukemia
3.      malignant melanoma
4.      kaposi’s sarcoma
5.      hepatitis B & C

Toxicity 

1.      fever
2.      chills
3.      myalgias
4.      headache
5.      depression
6.      myelosuppression

IL-2

1. Malignant melanoma
2. metastatic renal cell Carcinoma

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