Drug Combination in Cancer Treatment—From Cocktails to Conjugated Combinations

Abstract

It is well recognized today that anticancer drugs often are most effective when used in combination. However, the establishment of chemotherapy as key modality in clinical oncology began with sporadic discoveries of chemicals that showed antiproliferative properties and which as a first attempt were used as single agents. In this review we describe the development of chemotherapy from its origins as a single drug treatment with cytotoxic agents to polydrug therapy that includes targeted drugs. We discuss the limitations of the first chemotherapeutic drugs as a motivation for the establishment of combined drug treatment as standard practice in spite of concerns about frequent severe, dose limiting toxicities. Next, we introduce the development of targeted treatment as a concept for advancement within the broader field of small-molecule drug combination therapy in cancer and its accelerating progress that was boosted by recent scientific and technological progresses. Finally, we describe an alternative strategy of drug combinations using drug-conjugates for selective delivery of cytotoxic drugs to tumor cells that potentiates future improvement of drug combinations in cancer treatment. Overall, in this review we outline the development of chemotherapy from a pharmacological perspective, from its early stages to modern concepts of using targeted therapies for combinational treatment.

Histone deacetylase (HDAC) 9: versatile biological functions and emerging roles in human cancer

“…It is now widely recognized that therapeutic approaches that combine two or more agents can result in a synergistic effect through different mechanisms of action [145]. For example, HDAC9 inhibitors administered in combination with conventional anti-tumor agents or novel target-specific agents (that target known cancer-associated pathways for each type of cancer) may increase therapeutic efficacies.…”

Pentagalloyl Glucose and Cisplatin Combination Treatment Exhibits a Synergistic Anticancer Effect in 2D and 3D Models of Head and Neck Carcinoma

“…Several compounds from natural products have been reported to improve the therapeutic outcomes of cancer patients when used in combination with chemotherapeutic drugs. Combining these treatments can induce synergetic effects, inhibit side effects, or overcome drug resistance [ 7 , 8 , 11 ]. Previous studies have suggested the synergistic action of PGG with the traditional chemotherapeutic drug 5-FU in hepatocellular carcinoma.…”

“…It can target critical pathways in a synergistic or additive manner. This approach potentially reduces drug resistance and the chemotherapeutic drug doses in the regimen, helping to circumvent the severe side effects while providing anti-cancer benefits [ 7 , 8 ]. Increasing evidence has suggested that plant polyphenols might be combined with conventional therapy (chemo/radiotherapy) to sensitize tumor cells to the treatment by inhibiting the pathway that leads to treatment resistance [ 9 , 10 , 11 ].…”

Intracranial, intratumoral implantation of drug-releasing microdevices in patients with high grade gliomas is feasible, safe, and may predict tumor response to systemic chemotherapy

“…In addition to providing the ability to directly test a range of drugs in a patient, the use of IMDs in gliomas offer significant opportunities to answer questions which so far have been elusive: Firstly, this strategy allows to safely test the efficacy of drug combinations, which are commonly used in other cancers 37 , but only rarely in glioblastomas, despite significant preclinical evidence that different drugs acting synergistically against redundant oncogenes are more potent than single drugs 38,39 .…”