June 28, 2022

Recent developments in chemotherapy targeting could benefit patients

Because most chemotherapy drugs are quite toxic, doctors and patients need to carefully balance the risks and benefits of each treatment. To avoid dangerous toxicity, many of these drugs must be given in limited doses or a limited number of times, which can also limit their effectiveness.1Targeted cancer therapy includes several strategies that try to get around these limitations.1,2,3

What is targeted cancer therapy?

“Targeted” implies a treatment designed to maximally impact cancer cells, like an arrow aimed at a target, while causing much less harm to other tissues.2

Side effects of therapy for cancer depend on the agent but can include gastrointestinal distress and diarrhea, a weakened immune system, nerve damage and pain, easy bruising and bleeding, rashes, and other effects. Many of these side effects occur because traditional chemotherapy attacks all rapidly dividing cells, including cancerous and normal cells.2,3

Targeted therapy for cancer can help by reducing the amount of the drug that reaches healthy tissues and organs of the body. This can also increase the amount of drug that reaches the tumor cells and thus their cancer-fighting effectiveness.1 Types of targeted therapy for cancer Strategies include targeting molecules that are only present on or in cancer cells (molecular targeting), physically delivering the drug to the affected region (regional chemotherapy), and injecting the drug into the tumor itself (intratumoral chemotherapy).1,2 A newer, investigational method is chemical targeting using “click” chemistry.4 Molecularly targeted chemotherapy is the most common strategy. This involves finding or designing drugs or antibodies that bind to or block proteins found on cancer cells only or in higher abundance than on healthy cells. A large number of molecularly targeted drugs for various cancers are on the market in the US.2 Regional and localized chemotherapy Regional chemotherapy and localized chemotherapy strategies aim to deliver drugs to cancer cells by injecting or infusing the drug directly into the tumor or into its blood supply. These forms of targeted therapy for cancer can maximize the dose the cancer cells receive while minimizing adverse effects on the rest of the body.1 An example of regional chemotherapy is hepatic arterial infusion (HAI) chemotherapy, which is used for liver metastases from colorectal cancer.5 This strategy allows a 10- and 400-fold increase in tumor drug exposure, respectively, for fluorouricil (5-FU) and floxuridine (FUDR), two of the most commonly used HAI chemotherapy drugs.1 Intraperitoneal chemotherapy is a regional chemotherapy strategy used in combination with surgery to extend survival for patients with peritoneal carcinomatosis, which typically has a poor prognosis. The chemotherapy drug is heated (hyperthermic chemotherapy) to increase its effectiveness at killing cancer cells.1

Hyperthermic chemotherapy can also be used intratumorally. For example, injection of cisplatin heated between 40 and 45°C into tumors has been investigated as a palliative treatment for peripheral non-small cell lung cancer.6 In a small study, patients treated with intratumoral cisplatin along with systemic chemotherapy had increased survival when compared with the group given systemic chemotherapy alone.6 Intratumoral injection has also been investigated to relieve malignant airway obstruction in NSCLC.7

Other forms of intratumoral chemotherapy are being studied in mice.8 New strategies in targeted chancer therapy Chemical targeting using “click” chemistry – a group of techniques involving two partner molecules that are chemically reactive react only with each other- is a new approach under investigation. Tests in mice showed that doxorubicin, a low therapeutic index drug with severe side effects, could be tolerated at a cumulative dose more than fivefold higher when administered using a “click” chemistry method.10 A project currently in Phase 1 clinical trials involves an intratumoral injection with a biopolymer containing one of the partner molecules. Then, the patient is infused with the toxic chemotherapy drug doxorubicin in an inactive form, linked to the other partner molecule.4,9,10 A “click” reaction between the partners occurs, freeing and activating the drug within the tumor.4,9,10 If these strategies move to later stages of clinical development, they could help patients get more benefit from their chemotherapy with fewer side effects.1,4 References
  1. https://www.hcplive.com/view/a_brief_review_1009
  2. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies/targeted-therapies-fact-sheet
  3. https://www.medicalnewstoday.com/articles/323485#rare-side-effects
  4. https://www.discovermagazine.com/health/honeymoon-phase-chemical-partners-deliver-a-toxic-drug-to-tumors
  5. https://jamanetwork.com/journals/jamasurgery/article-abstract/2735967
  6. https://ejb.springeropen.com/articles/10.1186/s43168-020-00018-x
  7. https://pmj.bmj.com/content/98/1156/104
  8. https://pubs.acs.org/doi/10.1021/acs.molpharmaceut.0c00781
  9. https://clinicaltrials.gov/ct2/show/NCT04106492
  10. https://onlinelibrary.wiley.com/doi/epdf/10.1002/adtp.202000243
 

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