Cancer is a heterogeneous group of diseases characterized by uncontrolled cell proliferation exceeding that of normal corresponding cells and metastasis (Percorino, 2008; Mardis, 2012). An ideal chemotherapeutic agent is one that is selectively toxic to cancer cells in a regular and predictive manner (Henderson, 1969). Surgery and radiotherapy, two other therapeutic approaches to cancer are unable to reach delicate areas of cancer invasion, but systemic therapies (chemotherapy, hormone and targeted therapies) are the principal therapeutic regimes for metastatic disease (Caley & Jones, 2012).
Drawbacks to the use of chemotherapeutic agents fall on their limited effectiveness, their narrow therapeutic window which accounts for the numerous side effects experienced by patients, (due to their effect on normal rapidly dividing cells) and possibility of developing drug resistance (Workman, 2001).
Selective toxicity, Efficacy and side effect profile
Conventional chemotherapy agents including the antimitotic agents (doxorubicin; Figure 1) were identified with marked side effects due to their cytotoxic actions (Table 1) on multiple targets which extended to normal healthy cells (Priestman, 1989; Workman, 2001).
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Tailored with the side effects are their poor solubility and poor pharmacokinetics (Venditto et al, 2013).
Figure 1: Mechanism of doxorubicin toxicity summary (Adapted from Granados-Principal et al, 2010)
Table 1: Classification of chemotherapeutic agents, mechanism of action and examples (Adapted from Jones & Caley, 2012).
The toxicity of chemotherapy is a consequence of the drug itself, its dose, route and administration schedule; alopecia, myelosuppression, mucus membrane ulceration, nausea and vomiting are common toxicities (Caley & Jones, 2012). Although treatment cycles enable normal cells to recover, it nonetheless does not spare patients the unpleasant effects (Caley & Jones, 2012).
Palliative therapy with anti-emetics and dose reduction minimize toxicities (Caley & Jones, 2012).
The narrow therapeutic index and the life-threatening cardiotoxicity of cumulative adriamycin limits their efficacy in geriatrics while attempting to avoid the cardiotoxicity (Andreetta et al,2012).
Current approaches to side effects, low efficacy and selective toxicity:
Advances in nanomedicine (Figure 2) improve solubility, pharmacokinetics and toxicities of adriamycins (Venditto et al, 2013).
Encapsulation of doxorubicin in liposomes minimize toxicity and pegylation (caelyx) further reduces alopecia and vomiting whilst achieving better tumor targeting and longer circulation. (Andreetta et al, 2010).
Figure 2: Nanomedicine approaches to improving chemotherapy (Adapted from Shapira et al, 2011)
They enhance permeability, retention and inhibition of tumors (Figure 3) whilst taking advantage of the vasculature and lack of effective tumor lymph drainage in cancerous masses (Wu et al, 2006).
Figure 3: Tumor inhibition variance between encapsulated doxorubicin and the free drug (Adapted from Wan-Liang et al., 2004).
Although milder side effects exist, palmar-plantar erythrodysesthesia (PPE) is higher and represents a major drawback with caelyx (Alberts et al., 2004; Ewer et al., 2004; Ferrandina et al., 2010; Solomon and Gabizon, 2008). Palliative care neoadjuvant/adjuvant to cytotoxic drugs and management with anti-inflammatory agents and steroids provide relief (Caley & Jones, 2012).
Herceptin, a recombinant humanized monoclonal antibody targets over-expressed HER2 receptors (Figure 4) in breast cancers (BC) (Patani & Mokbel, 2010). This approach is devoid of alopecia, however, intra-tumor variations limit effectiveness long before the development of resistance; pre-screening is thus essential (Lee & Swanton, 2012).C:\Users\User\Desktop\1-s2.0-S0304383505001011-gr1.jpg
Figure 4: Illustration of the proposed mechanism of Herceptin (Adapted from Nahta & Esteva, 2006)
Drug resistance and treatment failure
Various gene mutations code for different proteins and as such various subtypes exist at the genetic and protein level for each case of BC, making difficult the task of choosing appropriate cytotoxic drugs (Pecorino, 2008; Cancer genome atlas network, 2012). Anon (2012) identified four major subtypes to BC at the genomic level and seven subtypes at the protein (The Cancer Genome Atlas Network, 2012).
Treatment failure caused by drug resistance is a combination of various resistance mechanisms to chemotherapy (Caley & Jones, 2012). Pecorino (2008) identifies the variation in the dose available to cells within the tumor masses as the cause; tumors away from blood supply or cells within the tumor coupled with individual cell mutations are responsible. Gottesman (2002) links host factors as causes of resistance i.e. rapid metabolism and poor tolerance especially in geriatrics.
Resistance to transtuzumab has been noted and linked to a number of pathways (Figure 5).
Figure 5: Proposed pathways to Transtuzumab resistance. Adapted from Nahta et al, 2006).
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Mutations affecting efflux transporters, decreasing intake of drugs, drug metabolism, DNA repair processes and loss of receptor as illustrated in figure 6 are also responsible for resistance to chemotherapy (Gottesman, 2002).
Mutations in P-glycoprotein efflux transporters are responsible for resistance to doxorubicin and vinblastin (Pecorino, 2008).
Drug resistance occurs due to the inter-dependence of pathways; targeting one pathway is likely to fail in cancer chemotherapy as resistance acquisition is fostered by intra-tumor genetic heterogeneity (Lee & Swanton, 2012).
Figure 6: Summary of mechanisms responsible for resistance
Current approaches to overcome resistance and treatment failure:
Combination therapy (CT) overcomes resistance, reduces fractional cell kill, compensate rewiring and improves the overall response rates (Priestman, 1989; Rebucci & Michaelis, 2013); doxorubicin and cisplatin have show synergistic action when combined compared to doxorubicin single therapy which severely induces resistance (Kusayanagi et al, 2012).
For metastatic disease and rapidly progressing disease, CT proves more effective; combination of chemotherapeutic agents with cyclophosphomide, doxorubicin and 5-fluorouracil has shown higher response rates (60%) and longer survival time (20 months) but at the risk of higher toxicities(Dunitz, 1993).
Combination of chemotherapy and molecular targeting drugs (Figure 7 & Figure 8) is important for remission/cure; CT in metastatic BC has to be the least toxic combination (Andreetta et al, 2010; Cross, 2005).
Combination with surgery and radiation may be beneficial: surgery with glidal wafer insertion have gained approval for glioblastomas (Venditto & Szoka, 2013).
The principles for generating combination therapies are:
Target various phases of cell cycle to achieve maximum cytotoxic action and with minimum risk of resistance.
Drugs with maximum efficacy are preferred but should have activity when using as single chemotherapy agents.
Mechanisms of action should vary to provide room for synergistic actions and optimal schedules and doses.
Minimum overlapping toxicity to patients should be achieved with reduction in life-threatening to particular organ systems.
Table 2: Principles governing choice of combination therapies (Adapted from Caley & Jones, 2012).
Figure 7: Targeted therapeutic approaches currently used and in trials (Adapted from Wu et al, 2006)
Figure 8: Some targeted approved therapeutic antibodies (Adapted from Wu et al, 2006)
Current research areas and what needs to be done by scientists:
The refinement of conventional chemotherapy as well as uncovering precise molecular targets (key markers) driving malignancy and genomic sequencing are ideal for developing personalized medicines (Workman, 2001; Patani & Mokbel, 2012).
Ongoing clinical researches in cancer genomics and viral delivery include:
Condition, sponsor and intervention
(Dana-Farber Cancer Institute)
Genetically modified cancer cells from patients (secreting GM-CSF)
Vaccines made from patient's cancer cells tested to identify vaccine's ability to delay/halt cancer progression.
(MD Anderson Cancer centre)
Tumor genetic biopsy to predict individual response to chemotherapy
Recruiting for Phase I
Identification of individual gene activation in HER2 negative and hormone therapy candidates to determine tumor sensitivity or resistance
Combination therapy with Trastuzumab, Cyclophosphamide , and personalized vaccine (GM-CSF-secreting)
Testing Cyclophosphamide ability to eliminate regulatory T cells suppression, Trastuzumab ability to increase antigen processing and presentation; to allow the immune system react better and enhance the effects of the vaccine in treating breast cancer.
Table 3: Ongoing clinical trials in breast cancer therapeutics (Adapted from Anon, 2013)
Pecorino (2008) mentioned the variability in response to chemotherapy as due to variance in gene expression among individuals with similar cancers. With the potential of the human genome to underpin novel anticancer development, extensive large scale sequencing of genomes representative of disguised cancers and approaches to develop mechanism based drugs targeting the anti-apoptotic pathways hold some benefit (Workman, 2001).
The development of personalised treatments are the future tools for improving the quality of life and overall survival of cancer patients (Lee & Swanton, 2012); paediatric patients and immunocompromised patients will benefit greatly from such innovation.
Genome based chemo-preventive therapy is another approach to be considered alongside safety (Workman, 2001) for high-risk patients.
Development of safe gene-based therapies (immune-stimulant genes and suicide genes) also hold potential (El-Aneed, 2004).
Kinases are identified as modern targets for small molecule drugs (Figure 9) as they are frequently deregulated in cancers; however, the inter-connection of various pathways render it difficult to not interfere with pathways unrelated to carcinogenesis (Workman, 2001).
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Isolation of peculiar pathways, markers and targeting will provide effective treatment of cancers.
Figure: Some mechanisms of small molecule inhibitors on kinases (Adapted from Wu et al, 2006)
Summary of areas to be covered by future work:
Limitation that will be overcome
Chemopreventive genome based medicines
This has the potential to overcome cancer development; identification of premalignancy genes and targeting them hold benefit as chemo-preventive therapies.
Targeting genes that promote drug resistance
In support of the current identification of the NEK2 resistance-promoting genes, the development of chemotherapeutics targeting such individual genes are capable of avoiding resistance
Antiangiogenic drugs and chemotherapy
Bocci & Loupakis (2012) propose the cause to resistance development to antiangiogenic drugs; clinical trials to test this hypothesis and to identification of the molecular basis of this could direct choice of combination therapies between antiangiogenic drugs and chemotherapeutics.
Role of nanovehicles
Development of theragnostic nanovehicles will achieve the following: selective targeting, malignant tumour diagnostic imaging, novel biological and chemo-sensitizing agents that will overcome various resistance mechanisms (Shapira et al, 2011).
Multidrug (MDR) resistance
MDR-protein and P-glycoprotein are capable of 'throwing out' various anticancer drugs; identification of lead compounds capable of bypassing and overcoming them will be beneficial. Identification of the link between these proteins and various cancer mechanisms is also beneficial (e.g. P53 protein) (Anon, 2000).
Reformulation of older efficacious chemotherapies as targeted drugs.
Chemotherapy has proved beneficial however; the numerous side effects limit their use and burden patients. Resistance and drug-related toxicity encompass the main limitations that prevent adequate efficacy and selective toxicity; although current advances have been beneficial, ongoing clinical trials and various hypothesis hold potentials to improve and treat metastatic and benign cancers regardless of the stage.