Targeted cellular metabolism for cancer chemotherapy with recombinant arginine-degrading enzymes

It has been shown that a subset of human cancers, notably, melanoma and hepatocellular carcinoma (HCC) are auxotrophic for arginine (Arg), because they do not express argininosuccinate synthetase (ASS), the rate-limiting enzyme for the biosynthesis of arginine from citrulline. These ASS-negative cancer cells require Arg from extracellular sources for survival. When they are exposed to recombinant Arg-degrading enzymes, e.g. arginine deiminase (ADI) or arginase, they die because of Arg starvation; whereas normal cells which express ASS are able to survive. A pegylated ADI (ADI-PEG20) has been developed for clinical trials for advanced melanoma and HCC; and favorable results have been obtained. ADI-PEG20 treatment induces autophagy in auxotrophic cancer cells leading to cell death. Clinical studies in melanoma patients show that re-expression of ASS is associated with ADI-PEG20 resistance. ADI-PEG20 treatment down-regulates the expression of HIF-1α but up-regulates c-Myc in culture melanoma cells. Induction of ASS by ADI-PEG20 involves positive regulators c-Myc and Sp4 and negative regulator HIF1α. Since both HIF-1α and c-Myc play important roles in cancer cell energy metabolism, together these results suggest that targeted cancer cell metabolism through modulation of HIF-1α and c-Myc expression may improve the efficacy of ADI-PEG20 in treating Arg auxotrophic tumors

Overcoming cisplatin resistance by mTOR inhibitor in lung cancer

BACKGROUND: Cisplatin resistance is complex and involves several different mechanisms. Employing cDNA microarray analysis, we have found that cisplatin resistant cells share the common characteristic of increase in ribosomal proteins and elongation factors. We hypothesize that in order to survive cisplatin treatment, cells have to synthesize DNA repair proteins, antiapoptotic proteins and growth-stimulating proteins. Thus, by blocking the translation of these proteins, one should be able to restore cisplatin sensitivity. We have studied the role of CCI-779, an ester analog of rapamycin which is known to inhibit translation by disabling mTOR, in restoring cisplatin sensitivity in a panel of cisplatin resistant cell lines. We have also determined the role of CCI-779 in P-gp1 and MRP1 mediated resistance. RESULTS: Our data show that CCI-779 possess antiproliferative effects in both cisplatin sensitive and resistant cell lines, but shows no effect in P-gp1 and MRP1 overexpressing cell lines. Importantly, CCI-779 at 10 ng/ml (less that 10% of the growth inhibitory effect) can increase the growth inhibition of cisplatin by 2.5–6 fold. Moreover, CCI-779 also enhances the apoptotic effect of cisplatin in cisplatin resistant cell lines. In these resistant cells, adding CCI-779 decreases the amount of 4E-BP phosphorylation and p-70S6 kinase phosphorylation as well as lower the amount of elongation factor while cisplatin alone has no effect. However, CCI-779 can only reverse P-gp mediated drug resistance at a higher dose(1 ug/ml). CONCLUSION: We conclude that CCI-779 is able to restore cisplatin sensitivity in small cell lung cancer cell lines selected for cisplatin resistance as well as cell lines derived from patients who failed cisplatin. These findings can be further explored for future clinical use. On the other hand, CCI-779 at achievable clinical concentration, has no growth inhibitory effect in P-gp1 or MRP1 overexpressing cells. Furthermore, CCI-779 also appears to be a weak MDR1 reversal agent. Thus, it is not a candidate to use in MDR1 or MRP1 overexpressing cells

The Florida Melanoma Trial I: A Prospective Multicenter Phase I/II Trial of Postoperative Hypofractionated Adjuvant Radiotherapy with Concurrent Interferon-Alfa-2b in the Treatment of Advanced Stage III Melanoma with Long-Term Toxicity Follow-Up

Radiotherapy (RT) and interferon-alfa-2b (IFN α-2b) have individually been used for adjuvant therapy stage III melanoma with high-risk pathologic features. We hypothesized that concurrent adjuvant RT and IFN α-2b may decrease the risk of regional recurrence following surgery with acceptable toxicity. A prospective multicenter phase I/II study was conducted to evaluate hypofractionated RT with concurrent IFN. Induction IFN α-2b, 20 MU/m2/d, was administered IV ×5 consecutive days every week for 4 weeks. Next, RT 30 Gy in 5 fractions was given with concurrent IFN α-2b, 10 MU/m2 SQ 3 times per week on days alternating with RT. Subsequent maintenance therapy consisted of adjuvant IFN α-2b, 10 MU/m2 SQ 3 times per week to a total of 1 year. To fully evaluate patterns of failure, long-term follow-up was conducted for up to 10 years. A total of 29 consenting patients were enrolled between August 1997 and March 2000. The maximum (worst) grade of acute nonhematologic toxicity during concurrent RT/IFN α-2b (and up to 2 weeks post RT) was grade 3 skin toxicity noted in 2 patients (9%). Late effects were limited. Probability of regional control was 78% (95% CI: 55%–90%) at 12 months. The median follow-up (range) was 80 (51–106) months among ten survivors (43%). The median overall survival was 34.5 months while the median failure-free survival was 19.9 months. Postoperative concurrent hypofractionated RT with IFN α-2b for advanced stage III melanoma appears to be associated with acceptable toxicity and may provide reasonable in-field control in patients at high risk of regional failure

Topoisomerase I inhibitors for the treatment of brain tumors

Patients with primary malignant brain tumors have a poor prognosis. Standard treatment includes surgical resection, radiation therapy and chemotherapy. Topoisomerase I inhibitors such as topotecan and irinotecan (CPT-11) represent one class of chemotherapy drugs that have been used in this disease. Recent clinical trials have shown major antitumor activity in recurrent glioblastoma when adding the antiangiogenesis drug bevacizumab with CPT-11. The combination of targeted agents to topoisomerase I inhibitors represent a novel and promising approach. This review will summarize clinical trials with topoisomerase I inhibitors and discuss new treatment strategies for primary malignant brain tumors

Pegylated arginine deiminase: a novel anticancer enzyme agent

Pegylated arginine deiminase (ADI-PEG20) is a novel anticancer enzyme that produces depletion of arginine, which is a nonessential amino acid in humans. Certain tumours, such as malignant melanoma and hepatocellular carcinoma, are auxotrophic for arginine. These tumours that are sensitive to arginine depletion do not express argininosuccinate synthetase, a key enzyme in the synthesis of arginine from citrulline. ADI-PEG20 inhibits human melanomas and hepatocellular carcinomas in vitro and in vivo . Phase I – II trials in patients with melanoma and hepatocellular carcinomas have shown the drug to have antitumour activity and tolerable side effects. Large Phase II trials and randomised, controlled Phase III trials are needed to determine its overall efficacy in the treatment of these malignancies and others