Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies

Pinto, Ana Catarina; Moreira, João Nuno; Simões, Sérgio

doi:10.5772/22656

Cited by 14 publications

(14 citation statements)

References 67 publications

(150 reference statements)

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“…One of them is that the doses used are administered at their maximum tolerated dose, leading to cumulative toxicity in both tumor and healthy tissues. Additionally, the overall result might not be the expected one, due to different biopharmaceutical properties (biodistribution, metabolization, elimination) of the associated active substances [7,8]. Considering these aspects, it is of critical importance that both active substances reach the target site at the same time and in the required concentration to exert the desired cytotoxic effect [5,8].…”

Section: Introductionmentioning

confidence: 99%

A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy

et al. 2021

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An increasing number of studies published so far have evidenced the benefits of Simvastatin (SIM) and Doxorubicin (DOX) co-treatment in colorectal cancer. In view of this, the current study aimed to investigate the pharmaceutical development of liposomes co-encapsulating SIM and DOX, by implementing the Quality by Design (QbD) concept, as a means to enhance the antiproliferative effect of the co-formulation on C26 murine colon cancer cells co-cultured with macrophages. It is known that the quality profile of liposomes is dependent on the critical quality attributes (CQAs) of liposomes (drug entrapped concentration, encapsulation efficiency, size, zeta potential, and drug release profile), which are, in turn, directly influenced by various formulation factors and processing parameters. By using the design of experiments, it was possible to outline the increased variability of CQAs in relation to formulation factors and identify by means of statistical analysis the material attributes that are critical (phospholipids, DOX and SIM concentration) for the quality of the co-formulation. The in vitro studies performed on a murine colon cancer cell line highlighted the importance of delivering the optimal drug ratio at the target site, since the balance antiproliferative vs. pro-proliferative effects can easily be shifted when the molar ratio between DOX and SIM changes.

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Section: Introductionmentioning

confidence: 99%

A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy

et al. 2021

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“…Hence, the most accurate CI determination is at the dose where 50% of cell growth is inhibited or in other words at the IC 50 value for each drug. 2 Overall, synergy was most commonly seen in MDA-MB-231 cells, where 5 of the 7 combinations displayed strong synergy (Figure 1a, S2A). The highest synergy in MDA-MB-231 cells was achieved at a ratio of 1:1 DOX:CPT (CI = 0.46 ± 0.06).…”

Section: Ratio-dependent Synergy Between Dox and Cptmentioning

confidence: 96%

“…Combination chemotherapy, in spite of its limitations, is the current gold standard for the treatment of advanced breast cancers. 1,2 A meta-analysis of several combination therapies for the treatment of metastatic breast cancer revealed that a heterogeneous yet statistically significant benefit was obtained for combination regimens in terms of tumor progression and overall survival. 3 Notwithstanding these improvements, the median survival times in combination treatment are still low and the survival benefits are counterbalanced with a proportional increase in the toxicity contributing to severe morbidity and poor quality of life for patients.…”

Section: Introductionmentioning

confidence: 99%

Role of synergy and immunostimulation in design of chemotherapy combinations: An analysis of doxorubicin and camptothecin

Pusuluri

Krishnan

et al. 2019

Bioengineering & Transla Med

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Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near‐their maximum tolerated doses (MTDs), elevating the risk of dose‐related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low‐dose treatment option for breast cancer. DOX‐CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA‐MB‐231). This combination led to excellent long‐term survival of mice bearing MDA‐MB‐231 tumors at doses roughly five‐fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX‐CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.

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“…The goal of combination chemotherapy is to intensify chemotherapy exposure by circumventing dose-limiting toxicity of single drugs and avoid the issue of resistance to a single chemotherapeutic drug, thereby ultimately increasing antitumour efficacy. It is thus fundamental to combine drugs that are active as single agents and have different mechanisms of action, resistance, and toxicity [120]. Advantages of this strategy include the potential to avoid treatment resistance, emergence of additive or synergistic effects, and reduction of drug dose with subsequent reduction of toxicity [120,121].…”

Section: Chemotherapymentioning

confidence: 99%

“…It is thus fundamental to combine drugs that are active as single agents and have different mechanisms of action, resistance, and toxicity [120]. Advantages of this strategy include the potential to avoid treatment resistance, emergence of additive or synergistic effects, and reduction of drug dose with subsequent reduction of toxicity [120,121]. Combination chemotherapy is undoubtedly pivotal for osteosarcoma treatment.…”

Section: Chemotherapymentioning

confidence: 99%

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

Lilienthal

Herold

2020

IJMS

206

140

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Osteosarcoma is the most common primary malignant bone tumour in children and adolescents. Due to micrometastatic spread, radical surgery alone rarely results in cure. Introduction of combination chemotherapy in the 1970s, however, dramatically increased overall survival rates from 20% to approximately 70%. Unfortunately, large clinical trials aiming to intensify treatment in the past decades have failed to achieve higher cure rates. In this review, we revisit how the heterogenous nature of osteosarcoma as well as acquired and intrinsic resistance to chemotherapy can account for stagnation in therapy improvement. We summarise current osteosarcoma treatment strategies focusing on molecular determinants of treatment susceptibility and resistance. Understanding therapy susceptibility and resistance provides a basis for rational therapy betterment for both identifying patients that might be cured with less toxic interventions and targeting resistance mechanisms to sensitise resistant osteosarcoma to conventional therapies.

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Combination Chemotherapy in Cancer: Principles, Evaluation and Drug Delivery Strategies

Cited by 14 publications

References 67 publications

A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy

A Screening Study for the Development of Simvastatin-Doxorubicin Liposomes, a Co-Formulation with Future Perspectives in Colon Cancer Therapy

Role of synergy and immunostimulation in design of chemotherapy combinations: An analysis of doxorubicin and camptothecin

Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies

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