39. Antineoplastic drugs: Biological therapy

Page created on June 5, 2019. Last updated on December 18, 2024 at 16:57

Summary

These drugs are not non-specifically cytotoxic like those in the previous topic but rather specific for some aspects of tumor cells. There are many types.

Monoclonal antibodies can bind to and antagonize growth factor receptors like HER2 on breast cancer. Trastuzumab binds to and inhibits HER2.

Drugs like imatinib can bind to and inhibit intracellular tyrosine kinases, which are especially characteristic for the Philadelphia chromosome in CML.

Drugs can bind to surface proteins of tumor cells and induce their death by antibody-dependant cellular cytotoxicity and complement activation. Rituximab binds to and kills B-cells in B-cell lymphomas.

Drugs can increase the anti-tumor effect of the immune system by inhibiting proteins that inhibit white blood cells. Nivolumab is an example.

Drugs can force tumor cells to differentiate into more mature and less malignant cells. Tretinoin can cause differentiation in acute promyelocytic leukaemia.

Hormone-sensitive tumors of the breast, prostate or endometrium can be treated with appropriate hormone-lowering drugs or hormone receptor antagonists. Tamoxifen blocks the oestrogen receptor in breast cancer. Finasteride blocks the enzyme that converts testosterone into DHT. Leuprolide or degarelix can cause chemical castration by inhibiting FSH and LH release from the pituitary.

Introduction to non-cytotoxic antineoplastic drugs

We’ve discussed the cytotoxic drugs, which are cytotoxic to all cells but mostly for tumor cells. We will now discuss the non-cytotoxic agents. These are not directly cytotoxic but rather inhibit mechanisms needed for growth and division of tumor cells specifically. As a result, they’re less toxic than cytotoxic drugs and therefore cause less side-effects.

We can distinguish two types of non-cytotoxic antineoplastic drugs:

• Biological agents – these drugs are biological in origin and affect certain biological processes in tumor cells
  • Cytokines with antitumor effect
  • Drugs binding to growth factor receptors and growth factors
  • Drugs inhibiting receptor tyrosine kinases
  • Drugs inhibiting intracellular tyrosine kinases
  • Antibodies against lymphocyte markers
  • Drugs that cause “disinhibition” of the immune system
  • Drugs that induce differentiation of tumor cells
  • Others
• Hormonal agents – drugs which only work on hormone-sensitive tumors

Many biological agents are monoclonal antibodies with specific targets.

Cytokines with antitumor effect

The important drugs here are recombinant human interferon α (rhIFN-α) and recombinant human interleukin 2 (rhIL-2).

Mechanism of action:

rhIFN-α, just like endogenous interferon α has antiproliferative and immunostimulant effect.

rhIL-2, just like endogenous IL-2 stimulates cytotoxic T-cells and NK-cells, which proceed to attack the tumor cells.

Side effects:

rhIFN-α can cause flu-like symptoms.

rhIL-2 increases vascular permeability, causing fluid loss to the interstitium with resulting hypovolaemia.

Drugs binding to growth factor receptors and growth factors

Many tumors express growth factor receptors and are stimulated by the presence of these growth factors. These drugs are only effective if the tumor expresses the growth factor receptor they act on. These drugs are monoclonal antibodies against these growth factor receptors or the growth factors themselves. Because they’re all monoclonal antibodies they all end with -mab.

• EGFR/HER1 inhibitor: cetuximab
• EGFR2/HER2 inhibitor: trastuzumab (Herceptin)
• VEGF inhibitor: bevacizumab
• VEGFR2 inhibitor: ramucirumab
• PDGFRA inhibitor: olaratumab

Indications:

Trastuzumab treats HER2 positive breast cancer.

Bevacizumab treats colorectal and renal cancer.

Mechanism of action:

EGFR is epidermal growth factor. VEGF is vascular endothelial growth factor and is involved in angiogenesis, which tumors obviously need a lot of. PDGF is platelet-derived growth factor.

When antibodies bind to the cell surface receptors, they not only block the ligand-binding site, but they also induce endocytosis of the receptor and stimulate antibody-dependent cellular cytotoxicity (ADCC), meaning that the immune system recognizes the antibody and kills the tumor cell.

Drugs inhibiting receptor tyrosine kinases

These drugs inhibit receptor tyrosine kinases, tyrosine kinases that are bound to growth factor receptors. They all have the -nib ending.

They are:

• 1^st gen. EGFR/HER1 inhibitor: erlotinib
• 2^nd gen. EGFR1-4 inhibitor: afatinib
• 3^rd gen. EGFR inhibitor: osimertinib
• EGFR+EGFR2 inhibitor: lapatinib
• ALK inhibitor: crizotinib
• VEGFR2 inhibitor: axitinib
• VEGFR+PDGFR+c-Kit inhibitor: sorafenib
• PDGFR+c-Kit inhibitor: imatinib
• VEGFR2+MET inhibitor: cabozantinib

Indications:

Erlotinib treats lung cancer with activating mutations in HER1.

Imatinib treats chronic myeloid leukaemia (CML).

Mechanism of action:

ALK stands for anaplastic lymphoma kinase. MET is the oncogene you might remember from patho; it’s a receptor for a growth factor called “mesenchymal-epithelial transition factor”.

Chronic myeloid leukaemia is characterised by the infamous Philadelphia chromosome, which encodes an always-active intracellular tyrosine kinase. Imatinib inhibits that intracellular tyrosine kinase.

By inhibiting these receptor tyrosine kinases, the growth factor receptors can’t transduce the signal into the cell, effectively inhibiting the receptor.

Antibodies against lymphocyte markers

The important drugs here are rituximab, alemtuzumab, daratumumab, elotuzumab, etc. Like the name suggests these drugs are monoclonal antibodies.

Indications:

Rituximab treats B-cell lymphomas, CLL and rheumatoid arthritis.

Mechanism of action:

These drugs bind to cell surface markers like CD20 and CD38. By binding those surface markers they induce the death of the target cell by three mechanisms:

• The complement system is activated, which lyses the target cell
• Antibody-mediated cellular cytotoxicity recruits NK-cells to kill the target cell
• The target cell undergoes apoptosis

Some of these drugs are antibodies conjugated with cytotoxic drugs. This allows the cytotoxic drugs to be targeted against whatever cell expresses the surface marker the antibody binds to.

Rituximab binds to CD20, a B-cell marker.

Agents that cause “disinhibition” of the immune system

An immune response always contains a balance between stimulatory and inhibitory signals, to prevent overstimulation. In the case of cancer therapy, inhibiting some of these inhibitory signals can be effective in increasing the anti-cancer response of the immune system.

These drugs are also called immune checkpoint inhibitors.

The important drugs here are ipilimumab, nivolumab and atezolizumab.

Indications:

Ipilimumab and nivolumab treat advanced melanoma.

Mechanism of action:

Ipilimumab binds to and blocks CTLA-4. This surface protein is found on regulatory T-cells. Its function is to inhibit T-cells. By blocking this inhibitory signal, T-cells are disinhibited, or stimulated.

Nivolumab bind to and blocks PD-1, a surface protein found on tumor cells which binds to PD-L1 on tumor-specific T-cells and triggers their apoptosis. By blocking this signal tumor-specific T-cells won’t die and can instead kill the tumor cell.

Drugs inducing differentiation of tumor cells

By causing tumor cells to differentiate into mature cells they will no longer be able to divide and cause harm. Several drugs can induce this differentiation, like tretinoin and arsenic trioxide.

Indications:

Tretinoin and arsenic trioxide treat acute promyelocytic leukaemia (APML).

Mechanism of action:

Tretinoin (all-trans retinoic acid) is a vitamin A derivative. The APML cells express an abnormal form of retinoic acid receptor which prevents retinoic acid from stimulating the cells to differentiate into mature cells. Tretinoin overcomes this and allows the cell to differentiate properly.

Arsenic trioxide stimulates the breakdown of the abnormal retinoic acid receptor, also allowing the cell to differentiate.

Side effects:

Tretinoin is highly teratogenic.

Other biological agents

Here we can include thalidomide, bortezomib and denileukin diftitox.

Indications:

Thalidomide and bortezomib treat multiple myeloma.

Denileukin diftitox treats T-cell lymphomas.

Mechanism of action:

Thalidomide reduces IL-6 and TNF-α levels (which normally stimulate myeloma cells) and enhances the activity of T-cells and NK cells.

Denileukin diftitox is actually a combination of IL-2 and diphtheria toxin. Only malignant lymphocytes express IL-2 receptor, so this drug carries diphtheria toxin to the tumor cells.

Mechanisms of resistance against antitumor agents

Tumors can develop resistance against certain antitumor agents. These mechanisms are often the result of mutations. If a small proportion of tumor cells in a tumor is resistant to the antitumor drug that the patient is currently being treated with, that population has an evolutionary advantage over the non-resistant tumor cells. The entire tumor will eventually be replaced by resistant cells.

There are many mechanisms that can mediate this resistance:

• Tumor cells can expel drugs out from the cells with the help of P-glycoprotein, a non-specific transporter
• Tumor cells can decrease their intake of the drug
• Tumor cells can decrease the intracellular metabolic activation of pro-drugs
• Tumor cells can increase its capacity for DNA repair
• Tumor cells can modify the enzyme the drug is targeting

Drugs used for chemoprevention of cancer

Some drugs be given to people with high-risk of developing cancer to prevent it from developing:

• NSAIDs – to prevent colorectal cancer
• Tamoxifen – to prevent ER-positive breast cancer
• Finasteride – to prevent prostate cancer

Appearently hormonal anti-cancer drugs aren’t part of the curriculum for pharma 2 (but rather for pharma 3), so you shouldn’t need to know anything below for the pharma 2 exam.

Hormonal agents

Hormonal agents are only effective on hormone-sensitive tumors. Some tumors express hormone receptors and depend on stimulation of these receptors for growth. By decreasing this stimulation, we can inhibit the growth of the tumor.

There are two ways to do this:

• Reduce the endogenous production of the hormone that stimulates the tumor
• Use a hormone antagonist to block the hormone receptor

In some other cases the hormonal drugs simply inhibit the growth of the tumor directly.

Glucocorticoids

Dexamethasone is the most important glucocorticoid drug in cancer therapy.

Indications:

Dexamethasone is used to treat ALL, lymphomas and multiple myeloma. It can also decrease the intracranial pressure and can therefore be helpful in treating brain tumors as well. It also lowers the serum calcium level and can therefore be used in patients with bone metastases. Lastly it can limit the nausea caused by cytotoxic agents.

Mechanism of action:

Glucocorticoids have an antiproliferative effect on lymphocytes.

Sex hormones and related compounds

When talking about hormone-sensitive tumors we usually mean breast, prostate or endometrial cancers that express oestrogen (ER), progesterone (PR) or androgen receptors (AR).

For these tumors we can use oestrogen analogues, oestrogen antagonists, oestrogen synthesis inhibitors, synthetic progesterones, antiprogesterones, androgen receptor antagonists, androgen synthesis inhibitors, GnRH agonists, GnRH antagonists, somatostatin analogues and dopamine receptor agonists.

Oestrogen analogues

Oestrogen analogues like ethinyl oestradiol and diethylstilboestrol (DES) will actually stimulate the growth of oestrogen receptor-producing tumors. This may seem like an unwanted effect, but with the combination of a cytotoxic drug this can actually increase the effect of a cytotoxic drug.

Oestrogen antagonists

This drug class is also called selective oestrogen receptor modulators (SERM) and includes tamoxifen, toremifene, raloxifene and fulvestrant.

Indications:

Oestrogen receptor-positive postmenopausal breast cancer. They can also be used for chemoprophylaxis of patients at high risk for developing this cancer.

Mechanism of action:

These drugs block the oestrogen receptor on the tumor cells, inhibiting their growth.

Side effects:

Tamoxifen and toremifene increase the risk of endometrial cancer, as they rather act as agonists and not antagonists on the endometrium. Raloxifene does not have this effect.

Inhibitors of oestrogen synthesis

These drugs don’t directly act on the tumor but rather decreases the level of oestrogen in the body, which indirectly decreases the growth of the tumor. The important drugs here are formestane, exemestane, anastrozole, letrozole and vorozole.

Indications:

Oestrogen receptor-positive breast cancer, especially for tamoxifen-resistant tumors.

Mechanism of action:

These drugs inhibit aromatase, the enzyme which converts androgens into oestrogens.

Synthetic progesterones/progestins

Progestins are synthetic progesterones. The important drugs here are medroxyprogesterone acetate and megestrol acetate.

Indications:

Metastatic endometrial and breast cancer.

Mechanism of action:

These drugs provide negative feedback on the pituitary, reducing the secretion of FSH and LH, which in turn decreases the level of oestrogen and androgens.

Antiprogesterones/antiprogestins

Only one important drug belongs to this class: mifepristone.

Indications:

Progesterone receptor-positive breast cancer. (according to the lecture, I don’t think it’s actually used for that)

Mechanism of action:

Competitive antagonist of progesterone receptors.

Androgen receptor antagonists

The important drugs here are flutamide, bicalutamide and nilutamide.

Indications:

These drugs are often used together with GnRH analogues/antagonists and orchidectomy to decrease androgen levels in patients with prostate cancer.

Mechanism of action:

These drugs are competitive antagonists of the androgen receptor.

Androgen synthesis inhibitors/5-alpha-reductase inhibitors

The important drugs here are finasteride and dutasteride.

Indications:

Therapy and chemoprevention of prostate cancer.

Mechanism of action:

These drugs inhibit 5-alpha-reductase, the enzyme that converts testosterone to the more potent dihydrotestosterone in the prostate.

GnRH agonists

The important drugs here are buserelin, goserelin, leuprolide and triptorelin.

Indications:

Breast cancer, prostate cancer.

Mechanism of action:

The synthetic GnRH agonists are many times more potent than endogenous GnRH. Giving GnRH agonists continuously causes an initial increase in FSH and LH, but after this the pituitary will downregulate GnRH receptors. This results in a decrease in FSH and LH secretion as long as the treatment continues. This is called medical or chemical castration.

GnRH antagonists

The important drug here is degarelix.

Indications:

Breast cancer, prostate cancer.

Mechanism of action:

These drugs inhibit FSH and LH secretion from the pituitary, decreasing the serum levels of androgens and oestrogens.

Somatostatin analogues

The important drugs here are octreotide and lanreotide.

Indications:

Gastrinoma, carcinoid syndrome, VIPoma, insulinoma, glucagonoma.

Mechanism of action:

These drugs are somatostatin analogues and therefore cause a somatostatin-mediated inhibition of hormone-secreting GI tumors.

Dopamine receptor agonists

The only important drug here is bromocriptine.

Indications:

Prolactinoma.

Mechanism of action:

Bromocriptine is a dopamine receptor agonist which inhibits proliferation of prolactin-producing cells.