Common Treatment Options For Cancer Patients

Published Date: 02 Nov 2017

Introduction

Chemotherapy is one of the most common treatment options for cancer patients. It involves treatment with one or more cytotoxic drugs. Unfortunately, the success of chemotherapy is limited by the low selectivity of these drugs in killing cancer cells as compared to normal cells resulting in side toxicity [1-2]. The problem is further aggravated due to abnormal tumor vasculature, tumors have leaky fragile blood vessels, loss of hierarchical vessel architecture causes increased interstitial pressure[3]. This results in hindered drug delivery to cancer cells, diminishing the effectiveness of this therapeutic modality [3-4]. Administration of higher drug doses is not a feasible option, as this increases the probability of severe side effects. Local administration of cytotoxic drugs directly into tumor tissue or into the major blood vessels feeding the tumor may results in enhancement of anti tumor activity, but this approach is limited to specific tumor locations, and does not target disseminated disease. New therapeutic strategies are needed to increase the effectiveness of systemic chemotherapy to improve cancer treatment outcomes. A study carried out by Leite et al. describes targeting prolyl hydroxylase domain protein 2(PHD2) as a potential option to improve chemotherapy [5]. This is one of the major discoveries in the past year, which would create a strong impact on cancer treatment.

Prolyl hydroxylase domain proteins (PHD) are enzymes that target the hypoxia inducible transcription factors (HIFs) for proteasomal degradation. The mode of action of these enzymes involves the utilization of oxygen to hydroxylate the alpha subunit of HIF-1 and HIF-2. PHDs also catalyze the hydroxylation of proline residues in many additional proteins and thus affect several biological functions including collagen formation, oxygen sensing, RNA transcription and NF-kB signaling[6]. When there is a drop in oxygen tension, PHDs become less active, leading to stabilization of HIF-2, resulting in initiation of an adaptive response involving angiogenesis, erythropoiesis and scavenging of reactive oxygen species (ROS)[7-9]. A recent study has shown that heterozygous deletion of Phd2 in mice leads to normalization of endothelial lining of the vessels, which is mediated by increased expression of HIF1 and HIF2[10]. The resulting change in vasculature structure and the shape of endothelial cells improves tumor perfusion and inhibits tumor metastasis [10].

Loss of Phd2: sensitizes tumor to chemotherapy. Leite et al. examined the effect of loss of Phd2 in endothelial cells on the delivery of chemotherapeutic drugs. Cisplatin and doxorubicin are the major used chemotherapeutic drugs. Wild Type (WT) and Phd2+/- mice bearing equal sized melanomas were subjected to a single dose of cisplatin. Platinum accumulation was measured in tumor, kidney and liver one hour after the drug administration. Intratumoral platinum was found to be higher in Phd2+/- mice as compared to WT mice. Interstitial fluid pressure is a physical property; increased fluid pressure hinders the transit of drugs within the tumor. Interstitial fluid pressure of Lewis lung adenocarcinomas (LLC) was decreased in the case of Phd2+/- mice as compared to the WT.

To test the effect of improved drug delivery on enhancement of anti-tumor activity, melanoma tumor bearing mice were treated with cisplatin. Phd2+/- mice showed a decrease in tumor volume and weight by 70%, with no effect on WT mice. In a similar study Phd2+/- mice bearing lung adenocarcinoma treated with doxorubicin. Phd2+/- mice showed decrease in tumor volume and weight by 60%. Moreover, doxorubicin treatment in Phd2+/- mice resulted in prevention of metastasis while there were no effects on metastasis in WT mice. Cisplatin treatment of melanoma tumors in Phd2+/- mice resulted in reduction of proliferation and promoted apoptosis of tumor cells. These results indicate that loss of Phd2 results in improved drug delivery and in enhancement of antitumor activity as compared to WT mice.

Loss of Phd2: detoxification of organs. Toxicity to normal organs is one of the biggest challenges of chemotherapy. Nephrotoxicity and cardiotoxicity [1-2] are some of major side effects of the therapy. Leite et al. compared the toxicity to healthy organs following administration of chemotherapy in WT and Phd2 +/- mice. In the kidney, acute cisplatin treatment for 3 days resulted in an increase in blood urea by 7.9 and creatinine by 21.9 times in WT mice as compared to 4.7 and 4.3 times, respectively, in Phd2+/- mice. Histological analysis of kidney sections showed several nephrological deformities in WT mice while Phd2+/- mice kidney sections appeared to be protected and were comparable to the kidneys from untreated mice. Analysis of cardiac performance following doxorubicin treatment showed similar trend. Acute treatment with doxorubicin for 5 days resulted in reduction in cardiac output by 22.3% in WT mice, while Phd2+/- mice showed no such effect. Histopathological analysis showed defects in the myofibers and signs of cardiomyopathy in WT mice, while these effects were rare and less extensive in case of Phd2+/- mice.

To address the issue that this haplodeficiency of Phd2 affect cells other than the endothelial cells, Leite et al then assessed the effect of deletion of single (PhdL/+) allele or deletion of both (PhdL/L) alleles. Mice were subjected to acute cisplatin or doxorubicin treatment. Results showed similar improvement in chemotherapy effectiveness with equal ability of PhdL/+ and PhdL/L mice to prevent cardiac and renal damage as compared to the WT mice.

Oxidative stress has been described as one of the mechanisms for toxicity to organs. Leite et al. further studied the effect of loss of Phd2 on antioxidative response. Kidney and heart sections were stained for 8-hydroxy deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Following acute cisplatin treatment, the number of nuclei showing 8-OHdG expression was 35 % in Phd2 +/- mice as compared to 53% in WT mice. Similar effects showing reduced oxidative damage in Phd2 +/- mice were seen following doxorubicin treatment. Furthermore, following acute treatment with cisplatin or doxorubicin, the activity of antioxidative enzymes was found to be significantly elevated in Phd2+/- mice compared to WT mice. They further demonstrated that the mechanism of protection of healthy organs by heterozygous deletion of Phd2 is mediated via activation of HIF-1 and HIF-2 that results in up-regulation of antioxidant enzymes. Furthermore, they found that induction of antioxidative enzymes was prevented when MnTBAP, a ROS scavenger was used, showing that ROS production as a result of chemotherapy i.e. on treatment with cisplatin/doxorubicin, is important for the detoxification response. Moreover, inhibition of Phd2 did not effect the antioxidant enzyme expression or ROS induction in vitro or in vivo in case of LLC cancer cells. These results indicate that a reduced level of PHD2 leads to effective antioxidative responses, in response to chemotherapy, only in normal organs but not in tumors.

Significance and future prospects. Chemotherapy is still one of the most common known treatment options for patients suffering from cancer. However, abnormal vasculature, dose limiting toxicity and resistance to the cytotoxic drugs are the biggest challenges, which limit chemotherapeutic effectiveness in clinic. Previous studies have shown that anti-angiogenic therapies including anti-VEGF/VEGFR (Vascular endothelial growth factor/receptor) approaches may be a therapeutic option to improve drug delivery considering their potential to promote normalization of tumor vessels in clinical studies [3, 11-12]. However, VEGF blockade also results in vessel pruning, which might lead to increase in hypoxia that can result in increased malignancy, with reduction of drug delivery and uptake [13]. A recent study has shown that bevacizumab, a monoclonal antibody against VEGF, results in decreased anti-cancer drug delivery to the tumor tissues [14]. Moreover, anti-angiogenic therapies alone can result resistance mechanisms [13]. A study has reported that the current angiogenic therapies are quite toxic, mainly when used in combination with chemotherapy [15]. Several alternative approaches to improve drug delivery either by normalizing blood vessels [16-18] or by directed tumor specific delivery [19] have been evaluated but have not shown efficient desired effect.

Leite et al. have shown the advantage of targeting PHD2 over anti-angiogenic therapies. Targeting PHD2 would lead to improve chemotherapy via two mechanisms: 1) the normalization of tumor vasculature resulting in improved drug delivery and 2) the enhancement of HIF mediated detoxification response in organs (Figure 2). Moreover, administration of chemotherapeutic drugs in Phd2+/- mice improves metastatic inhibition, and vessels in Phd2+/- mice have shown better functionality both before and after the chemotherapy suggesting no acquisition of resistance.

Decreased activity of PHD2 in endothelial cells results in improved chemotherapy. On the other hand, in healthy organs, increased ROS levels due to chemotherapy hampers PHD2 activity resulting in stabilization of HIF-1 and HIF-2, which further results in transcription of genes that code for antioxidative enzymes. This acts as an in built mechanism to reduce tissue damage. Genetic deletion of Phd2 further decreases the threshold of HIFs activation, which contributes to this feedback loop resulting in prevention of organ failure and tissue damage. Thus, targeting PHD2 offers a dual advantage in cancer treatment. However, as a potential drawback, activation of HIF-1 and HIF-2 due to the loss of PHD2 might affect the regulation of energy metabolism and redox mechanisms in tumor stroma. Recent studies have suggested the role of tumor stromal cell interaction in affecting the ROS levels in cancer cells. PHD2 may affect these interactions; it will be interesting to determine if PHD2 has a role in regulating these interactions [20-22].

This study provides a rationale for molecular targeting of PHD2. There are various prolyl hydroxylases, which affect different biological functions. WT mice treated with dimethyloxaloylglycine (DMOG) a nonspecific inhibitor of prolyl hydroxylases showed similar effects as inactivation of Phd2, however, specific inhibitors against PHD2 should be developed for successful targeting. Inhibitors against PHD2 are commercially not available[23], but several screening strategies have been developed. Studies should be developed for clinical testing of these drugs in mouse models in combination with chemotherapy. Considering the results demonstrated by Leite et al. targeting PHD2 may prove to be a major discovery in the forthcoming decade in terms of improving the effectiveness of chemotherapy for cancer treatment.