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SummaryDuring treatment, the development of drug-resistant tumours remains an important challenge in cancer treatment. Epigenetic changes have been reported as one of the mechanisms for anti-tumour drug resistance. In clinical practice, a combination of epigenetic-related drugs can be considered as a future selection of cancer therapeutic drugs.

Background: The immune system has a central role in controlling cancer, and factors that influence protective antitumour immunity could therefore have a significant impact on the course of malignant disease. Opioids are essential for the management of cancer pain, and preclinical studies indicate that opioids have the potential to influence these tumour immune surveillance mechanisms. The aim of this systematic literature review is to evaluate the clinical effects of opioids on the immune system of patients with cancer. Methods: A systematic search of Ovid MEDLINE (PubMed) and Embase, Cochrane database and Web of Knowledge for clinical studies, which evaluated the effects of opioids on the immune system in patients with cancer, was performed. Results: Five human studies, which have assessed the effects of opioids on the immune system in patients with cancer, were identified. Although all of these evaluated the effect of morphine on immunologic end points in patients with cancer, none measured the clinical effects. Conclusions: Evidence from preclinical, healthy volunteer and surgical models suggests that different opioids variably influence protective anti-tumour immunity; however, actual data derived from cancer populations are inconclusive and definitive recommendations cannot be made. Appropriately designed and powered studies assessing clinical outcomes of opioid use in people with cancer are therefore required to inform oncologists and others involved in cancer care about the rational use of opioids in this patient group.

Background: Reovirus preferentially infects and kills cancer cells and is currently undergoing clinical trials internationally. While oncolysis is the primary mode of tumour elimination, increasing evidence illustrates that reovirus additionally stimulates anti-tumour immunity with a capacity to target existing and possibly relapsing cancer cells. These virus-induced anti-tumour immune activities largely determine the efficacy of oncotherapy. On the other hand, anti-viral immune responses can negatively affect oncotherapy. Hence, the strategic management of anti-tumour and anti-viral immune responses through complementary therapeutics is crucial to achieve the maximum anti-cancer benefits of oncotherapy. Methods: Intra-peritoneal injection of mouse ovarian surface epithelial cells (ID8 cells) into wild-type C57BL/6 mice was treated with a therapeutic regimen of reovirus and/or gemcitabine and then analysed for prolonged survival, disease pathology, and various immunological parameters. Furthermore, in vitro analyses were conducted to assess apoptosis, viral spread, and viral production during reovirus and/or gemcitabine treatment. Results: We demonstrate that reovirus and gemcitabine combination treatment postpones peritoneal carcinomatosis development and prolongs the survival of cancer-bearing hosts. Importantly, these anti-cancer benefits are generated through various immunological mechanisms, including: (1) inhibition of myeloid-derived suppressor cells recruitment to the tumour microenvironment, (2) downmodulation of pro-MDSC factors, and (3) accelerated development of anti-tumour T-cell responses. Conclusion: The complementation of reovirus with gemcitabine further potentiates virus-initiated anti-cancer immunity and enhances the efficacy of oncotherapy. In the context of ongoing clinical trials, our findings represent clinically relevant information capable of enhancing cancer outcomes.

Background: Survivin, a member of the inhibitor of apoptosis protein family, is an attractive target for cancer therapy. We have now investigated the effects of the combination of YM155, a novel small-molecule inhibitor of survivin expression, and platinum compounds (cisplatin and carboplatin) on human non-small cell lung cancer (NSCLC) cell lines. Methods: The anti-cancer efficacy of YM155 in combination with platinum compounds was evaluated on the basis of cell death and progression of tumour xenografts. Platinum compound-induced DNA damage was evaluated by immunofluorescence analysis of histone γ-H2AX. Results: Immunofluorescence analysis of histone γ-H2AX showed that YM155 delayed the repair of double-strand breaks induced in nuclear DNA by platinum compounds. The combination of YM155 and platinum compounds also induced synergistic increases both in the number of apoptotic cells and in the activity of caspase-3. Finally, combination therapy with YM155 and platinum compounds delayed the growth of NSCLC tumour xenografts in nude mice to an extent greater than that apparent with either treatment modality alone. Conclusion: These results suggest that YM155 sensitises tumour cells to platinum compounds both in vitro and in vivo, and that this effect is likely attributable to the inhibition of DNA repair and consequent enhancement of apoptosis.

Omlin et al (2013) report the anti-tumour activity of diethylstilbestrol (DS) and abiraterone (AA) in castration-resistant prostate cancer and suggest substantial activity of AA in DS pretreated patients. Their retrospective review includes patients who were post docetaxel as well as those who were chemotherapy naive. We feel that the additional activity of AA may have been overstated. Abiraterone is always combined with a corticosteroid – and therefore the comparison is between AA and a corticosteroid vs DS and a corticosteroid. Most of the patients in the series described by Omlin et al (2013) received DS without a corticosteroid. In the paper by Ryan et al (2013) median time to progression (TTP) was doubled when AA and prednisone was compared with prednisone alone (11.1 vs 5.6 months). When the combination of dexamethasone and DS was compared to dexamethasone alone, a similar effect was seen (8.6 vs 4.5 months) in chemotherapy-naive patients (Shamash et al, 2011), see table below.

The use of β-blockers for the management of hypertension has been recently associated with significant clinical benefits in cancer patients. Herein, we investigated whether β-blockers could be used in combination with chemotherapy for the treatment of neuroblastoma.Seven β-blockers were tested for their antiproliferative and anti-angiogenic properties alone, and in combination with chemotherapy in vitro; the most potent drug combinations were evaluated in vivo in the TH-MYCN mouse model of neuroblastoma.Three β-blockers (i.e., carvedilol, nebivolol and propranolol) exhibited potent anticancer properties in vitro and interacted synergistically with vincristine, independently of P-glycoprotein expression. β-blockers potentiated the anti-angiogenic, antimitochondrial, antimitotic and ultimately pro-apoptotic effects of vincristine. In vivo, β-blockers alone transiently slowed tumour growth as compared with vehicle only (P0.01). More importantly, when used in combination, β-blockers significantly increased the tumour regression induced by vincristine (P0.05). This effect was associated with an increase in tumour angiogenesis inhibition (P0.001) and ultimately resulted in a four-fold increase in median survival, as compared with vincristine alone (P0.01).β-blockers can increase treatment efficacy against neuroblastoma, and their combination with chemotherapy may prove beneficial for the treatment of this disease and other drug-refractory cancers.

Comment on ‘Beta-blockers increase response to chemotherapy via direct anti-tumour and anti-angiogenic mechanisms in neuroblastoma’

FCE 23762 is a new doxorubicin derivative obtained by appending a methoxymorpholinyl group at position 3' of the sugar moiety. The compound is greater than 80 times more potent than doxorubicin, it is highly lipophilic, and presents equivalent anti-tumour activity when administered by i.p., i.v. or oral route. The pattern of anti-tumour activity of FCE 23762 differs from that of doxorubicin in maintaining anti-tumour activity against two P388 murine leukaemia sublines resistant to doxorubicin and, although at borderline levels of efficacy, against LoVo human colon adenocarcinoma resistant to doxorubicin. FCE 23762 exhibits remarkable efficacy against MX-1 human mammary carcinoma, with most treated mice being cured both after i.v. and oral treatment. Anti-tumour activity was also observed against L1210 murine leukaemia and two sublines resistant to cis-platinum and melphalan, M5076 murine reticulosarcoma, MTV murine mammary carcinoma and N592 human small cell lung cancer.

A malignant invasive fibrosarcoma in hamsters and a malignant mammary carcinoma in mice were each challenged with the broad spectrum proteinase inhibitor aprotinin (Trasylol). In both tumour systems, significant anti-tumour effects of aprotinin were observed. Variations in the site and dosage of aprotinin application were made in an attempt to improve the chemotherapeutic response. ImagesFig. 1Fig. 2

Experiments were undertaken with DMBA-induced mammary tumours of the rat to determine the anti-tumour properties of a new and potent luteinizing hormone releasing hormone (LH-RH) agonist, [D-Ser(But) 6Azgly10]-LH-RH (ICI 118630). Tumours were classified according to their oestrogen-receptor (ER) content. Twice daily i.m. injections of either 5 micrograms or 0.5 micrograms ICI 118630 in saline were as effective as ovariectomy or tamoxifen therapy in causing the regression of ER+ DMBA-induced mammary tumours. ER- mammary tumours showed a more equivocal overall response to ICI 118630, some tumours progressing, others regressing. About one-third of the ER+ tumours disappeared in the 20-day treatment period. Those tumours which did regrow after the cessation of treatment proved to be hormone-dependent. In addition to the inhibitory effects of the LH-RH agonist on pre-existing tumours, ICI 118630 also reduced the total number of new tumours formed during and after treatment.

The anti-tumour action of methylene dimethane sulphonate (MDMS) has been further investigated in relation to its immunosuppressive properties. Following a dose of 10 mg/kg, the proportion of permanent regressions of Yoshida lymphosarcoma transplants is lower in animals treated during the first 5 days of tumour growth. Re-implants on day 28 to those animals in which regression of the tumour had occurred indicated that the immune response to the tumour increases during the first 7 days of tumour growth. Studies of the effect of MDMS on the primary antibody-forming cell response of mice to sheep red cell antigens showed this drug to be an immunosuppressant comparable in strength to x-radiation. MDMS given to rats prior to tumour transplantation also acted as an immunosuppressant in this system resulting in an increased rate of tumour growth. For both responses the maximum immunosuppressive effect was obtained when the interval between drug administration and antigenic challenge was minimal.

Some Biological and Clinical Results from the Investigations of the Chloroethylamines as Anti-Tumour Drugs *

Production of an anti-tumour cytotoxin by human monocytes: Comparison of endotoxin, interferons and other agents as inducers

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Chinese hamster ovary cells have been treated in vitro with the platinum coordination complexes cis-PAD or CHIP and with radiation, either alone or in combination with different doses and time intervals. The isobologram method has been used to make a graphic comparison of these combined-modality data in terms of additivity and enhancement. The data showed enhancement of the radiation effect by these platinum complexes in many combinations, and a truly synergistic effect in one case. This method of analysis points to the limited usefulness of the parameter dose-modifying effect (DMF) since the most synergistic combination did not have the highest DMF.