Why Concurrent CDDP and Radiotherapy Has Synergistic Antitumor Effects: A Review of In Vitro Experimental and Clinical-Based Studies.

Chemo-radiotherapy, which combines chemotherapy with radiotherapy, has been clinically practiced since the 1970s, and various anticancer drugs have been shown to have a synergistic effect when used in combination with radiotherapy. In particular, cisplatin (CDDP), which is often the cornerstone of multi-drug combination cancer therapies, is highly versatile and frequently used in combination with radiotherapy for the treatment of many cancers. Therefore, the mechanisms underlying the synergistic effect of CDDP and radiotherapy have been widely investigated, although no definitive conclusions have been reached. We present a review of the combined use of CDDP and radiotherapy, including the latest findings, and propose a mechanism that could explain their synergistic effects. Our hypothesis involves the concepts of overlap and complementation. "Overlap" refers to the overlapping reactions of CDDP and radiation-induced excessive oxidative loading, which lead to accumulating damage to cell components, mostly within the cytoplasm. "Complementation" refers to the complementary functions of CDDP and radiation that lead to DNA damage, primarily in the nucleus. In fact, the two concepts are inseparable, but conceptualizing them separately will help us understand the mechanism underlying the synergism between radiation therapy and other anticancer drugs, and help us to design future radiosensitizers.

Triggered radiosensitizer delivery using thermosensitive liposomes and hyperthermia improves efficacy of radiotherapy: An in vitro proof of concept study.

INTRODUCTION: To increase the efficacy of chemoradiation and decrease its toxicity in normal tissue, a new concept is proposed, local radiosensitizer delivery, which combines triggered release of a radiosensitizer from thermosensitive liposomes with local hyperthermia and radiotherapy. Here, key aspects of this concept were investigated in vitro I) the effect of hyperthermia on the enhancement of radiotherapy by ThermoDox (thermosensitive liposome containing doxorubicin), II) the concentration dependence of the radiosensitizing effect of doxorubicin and III) the sequence of doxorubicin, hyperthermia and radiotherapy maximizing the radiosensitizing effect. METHODS: Survival of HT1080 (human fibrosarcoma) cells was measured after exposure to ThermoDox or doxorubicin for 60 minutes, at 37 or 43°C, with or without irradiation. Furthermore, cell survival was measured for cells exposed to different doxorubicin concentrations and radiation doses. Finally, cell survival was measured after applying doxorubicin and/or hyperthermia before or after irradiation. Cell survival was measured by clonogenic assay. In addition, DNA damage was assessed by γH2AX staining. RESULTS: Exposure of cells to doxorubicin at 37°C resulted in cell death, but exposure to ThermoDox at 37°C did not. In contrast, ThermoDox and doxorubicin at 43°C resulted in similar cytotoxicity, and in combination with irradiation caused a similar enhancement of cell kill due to radiation. Doxorubicin enhanced the radiation effect in a small, but significant, concentration-dependent manner. Hyperthermia showed the strongest enhancement of radiation effect when applied after irradiation. In contrast, doxorubicin enhanced radiation effect only when applied before irradiation. Concurrent doxorubicin and hyperthermia immediately before or after irradiation showed equal enhancement of radiation effect. CONCLUSION: In vitro, ThermoDox resulted in cytotoxicity and enhancement of irradiation effect only in combination with hyperthermia. Therefore hyperthermia-triggered radiosensitizer release from thermosensitive liposomes may ultimately serve to limit toxicities due to the radiosensitizer in unheated normal tissue and result in enhanced efficacy in the heated tumor.

Phase 1/2 Study of the Addition of Cisplatin to Adjuvant Chemotherapy With Image Guided High-Precision Radiation Therapy for Completely Resected Gastric Cancer.

PURPOSE: Locoregional recurrence is common after surgery for gastric cancer. Adjuvant therapy improves outcomes but with toxicity. This phase 1/2 study investigated infusional 5-fluorouracil (5-FU) in combination with biweekly cisplatin delivered concurrently with image guided high-precision radiation therapy. METHODS AND MATERIALS: Eligible patients had completely resected stage IB to IV (Union for International Cancer Control TNM 6th edition) nonmetastatic gastric adenocarcinoma. Treatment constituted 12 weeks of infusional 5-FU (200 mg/m2/day) with cisplatin added in a standard 3 + 3 dose escalation protocol (0, 20, 30, and 40 mg/m2) during weeks 1, 3, 5, and 7, and an additional week 9 dose in the final cohort. Radiation therapy (45 Gy in 25 fractions) was delivered during weeks 3 to 7. Maximum tolerated dose (MTD) was determined in phase 1 and confirmed in phase 2. RESULTS: Among the 55 patients (median age, 54 years; range 28-77 years; 55% male), the median follow-up time was 3.0 years (range, 0.3-5.3 years). Five patients in phase 1 experienced dose-limiting toxicity, and MTD was determined as 4 cycles of 40 mg/m2 cisplatin. Twenty-seven patients were treated at MTD. Acute grade 3 to 4 toxicity rate was 37.0% at MTD and 29.1% across all dose levels. No treatment-related deaths occurred. Fourteen patients experienced recurrent disease. The 2-year overall survival (OS) and relapse-free survival were 85% and 74%, respectively. Median OS has not been reached. Quality of life (QOL) was impaired during treatment, but most scores recovered by 4 weeks. CONCLUSION: Cisplatin can be safely delivered with 5-FU-based chemoradiation therapy. Acute toxicity was acceptable, and patient-reported QOL showed the regimen was tolerable. Outcomes are encouraging and justify further study of this regimen.

Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study.

PURPOSE: The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), particularly the role of concurrent chemoradiotherapy (CCRT), remains debatable. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with unresectable LAPC. MATERIALS AND METHODS: Patients with LAPC who were consecutively treated between 2003 and 2010 were included. Resectability was evaluated according to National Comprehensive Cancer Network ver. 1.2012. The clinical outcomes for each treatment group (CCRT vs. CA) were evaluated retrospectively. RESULTS: Sixty-three patients (58.9%) and 44 patients (41.1%) were treated with CCRT and CA, respectively. The CCRT cohort included patients who were treated with CCRT with or without chemotherapy backbone (CCRT alone, induction chemotherapy-CCRT, CCRT-maintenance chemotherapy, and induction-CCRT-maintenance chemotherapy). Median progression-free survival (PFS) and overall survival (OS) of all patients were 7.2 months and 13.1 months. PFS of the CCRT and CA groups was 9.0 months and 4.4 months, respectively (p=0.020). OS of the CCRT and CA groups was 15.4 months and 9.3 months, respectively (p=0.011). In multivariate analysis, the adjusted hazard ratio of CCRT was 0.536 (p=0.003) for OS and 0.667 (p=0.078) for PFS. Although the pattern of failure was similar in the CCRT and CA groups, the times to both local and distant failure were significantly longer in the CCRT group. CONCLUSION: In patients with unresectable LAPC, those who underwent CCRT during their entire treatment courses had longer OS than patients treated with chemotherapy alone.

A Phase 2 Study of Concurrent Radiation Therapy, Temozolomide, and the Histone Deacetylase Inhibitor Valproic Acid for Patients With Glioblastoma.

PURPOSE: Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor (HDACi) activity shown to sensitize glioblastoma (GBM) cells to radiation in preclinical models. We evaluated the addition of VPA to standard radiation therapy (RT) plus temozolomide (TMZ) in patients with newly diagnosed GBM. METHODS AND MATERIALS: Thirty-seven patients with newly diagnosed GBM were enrolled between July 2006 and April 2013. Patients received VPA, 25 mg/kg orally, divided into 2 daily doses concurrent with RT and TMZ. The first dose of VPA was given 1 week before the first day of RT at 10 to 15 mg/kg/day and subsequently increased up to 25 mg/kg/day over the week prior to radiation. VPA- and TMZ-related acute toxicities were evaluated using Common Toxicity Criteria version 3.0 (National Cancer Institute Cancer Therapy Evaluation Program) and Cancer Radiation Morbidity Scoring Scheme for toxicity and adverse event reporting (Radiation Therapy Oncology Group/European Organization for Research and Treatment). RESULTS: A total of 81% of patients took VPA according to protocol. Median overall survival (OS) was 29.6 months (range: 21-63.8 months), and median progression-free survival (PFS) was 10.5 months (range: 6.8-51.2 months). OS at 6, 12, and 24 months was 97%, 86%, and 56%, respectively. PFS at 6, 12, and 24 months was 70%, 43%, and 38% respectively. The most common grade 3/4 toxicities of VPA in conjunction with RT/TMZ therapy were blood and bone marrow toxicity (32%), neurological toxicity (11%), and metabolic and laboratory toxicity (8%). Younger age and class V recursive partitioning analysis (RPA) results were significant for both OS and PFS. VPA levels were not correlated with grade 3 or 4 toxicity levels. CONCLUSIONS: Addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated. Additionally, VPA may result in improved outcomes compared to historical data and merits further study.

Ascorbic acid glucoside reduces neurotoxicity and glutathione depletion in mouse brain induced by nitrotriazole radiosensitazer.

AIM: To investigate the potential of the anti-oxidant ascorbic acid glucoside (AA-2G) to modulate neurotoxicity induced by high doses of nitrotriazole radiosensitizer. MATERIALS AND METHODS: Male and female C56Bl/6xCBA hybrid mice aged 8-14 weeks (weight 18-24 g) were used. Nitrotriazole drug radiosensitizer sanazole at a high dose of 2, 1 g/kg was per os administered to induce neurotoxicity at mice. Ascorbic acid glucoside was given 30 min before the sanazole administration. Serum ascorbic acid, brain glutathione level, as well as behavioral performance using open field apparatus were measured. RESULTS: Administration of high (non-therapeutic) doses of the nitrotriazole drug sanazole results in neurotoxicity in mice as evidenced from behavioral performance, emotional activity and depletion of the cellular antioxidant, glutathione, in the brain. The serum levels of ascorbic acid was also found reduced in high dose sanazole treated animals. Per os administration of ascorbic acid glucoside significantly reduced the neurotoxicity. This effect was associated with the prevention of glutathione depletion in mouse brain and restoring the ascorbic acid level in serum. CONCLUSION: Administration of ascorbic acid glucoside, but not ascorbic acid, before sanazole administration protected from sanazole-induced neurotoxicity by preventing the decrease in the brain reduced glutathione level and providing high level of ascorbic acid in plasma.

Vitamin B2: a promising adjuvant in cisplatin based chemoradiotherapy by cellular redox management.

Cancer has been a big challenge in the clinical research arena for many years. All the major anticancer drugs are either not effective or induce serious side effects. Cisplatin (CP) is one of the most valued anticancer drugs against various forms of cancer but it exerts many side effects often resulting in withdrawal of clinical usage during long-term chemotherapy. Thus, increasing the efficacy of the drugs and minimizing deleterious side effects is needed. Vitamins like riboflavin (RF) are promising under photodynamic therapy in this aspect because of its potential as an efficient adjuvant confirmed in many cancer cell lines and animal-based studies. It has been found to alleviate CP-induced side effects significantly under photoillumination in mice. As CP exerts most of its toxic effects by oxidative and nitrosative stress; clubbing ribophototherapy with chemotherapy involving CP can shift the redox status favoring better cancer treatment. This strategy can not only increase the average life span of the cancer patients but also improve their quality of life significantly. However, cancer is still considered as a disease of genetic and metabolic disorders; hence, attacking both aspects of the disease can give better results as compared to contemporary treatment modalities.

Methylenetetrahydrofolate reductase genetic polymorphisms and toxicity to 5-FU-based chemoradiation in rectal cancer.

BACKGROUND: There is a large degree of variation in tumour response and host toxicities associated with neoadjuvant chemoradiation for rectal cancer patients. We performed a complimentary pharmacogenetic study to investigate germline polymorphisms of genes involved in 5-fluorouracil (5-FU) and irinotecan pathways and their potential association with clinical outcomes and toxicities from neoadjuvant chemoradiation in patients with rectal cancer treated in a prospective genotype-directed study. METHODS: The germline DNA of 131 patients was genotyped for 10 variants in TYMS, MTHFR, DPYD, UGT1A1, ABCC1 and SLCO1B1 genes. Ninety-six patients were treated with 5-FU/radiotherapy (RT) and 35 received 5-FU/RT/irinotecan. Relationships between genetic variants and adverse events, tumour response, overall and disease-free survivals were assessed. RESULTS: MTHFR 1298A>C and MTHFR diplotypes (for 677C>T and 1298A>C) were associated with chemoradiation-related toxicity when 5-FU was used alone. MTHFR haplotypes (677C-1298C) and diplotypes (CA-TA and TA-TA) showed, respectively, a protective and a negative effect on the incidence of severe diarrhoea or mucositis. No association was observed between genetic markers and drug response. CONCLUSION: MTHFR polymorphisms can potentially predict toxicity in patients treated with 5-FU as a single chemotherapeutic drug.

[Effectiveness of neoadjuvant chemoradiotherapy of locally advanced rectal cancer in conjunction with local hyperthermia and metronidazole].

Our study included 36 patients with hard fixed rectal tumors (T3, T4) who had received combined treatment at the Center's Clinics. On irrigoscopic evidence, lesions were more than 10 cm long. Radiotherapy was conducted thrice a week, STD of 4 Gy--TTD of 40 Gy; capecitabine, per os, 650 mg/m2 twice a day, days 1-22; oxaliplatin, 50 mg/m2, intravenously, days 3, 10 and 17; metronidazole in polymer composition, intrarectally, 10 mg/m2, twice, days 12 and 17 of radiotherapy; local hyperthermia (the <> installation), 460 mHz, 41-45 deg. C, 60 min, days 8, 12, 15 and 17. Diarrhea (stage III) was reported in 3 (8.3%); no toxicity (grade IV). Radical surgery was carried out in 35 (97.2%); sphincter-saving operation--20 (55.5%). Therapy-related pathomorphism (grade III-IV) was detected in 15 (42.8%). Combined neoadjuvant chemoradiotherapy plus polyradiomodification featured low toxicity and good tolerability and immediate effect.

Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer.

BACKGROUND: Capecitabine is an attractive radiosensitizer. In this study acute toxicity and surgical complications were evaluated in patients with locally advanced rectal cancer following total mesorectal excision (TME) after preoperative chemoradiotherapy (CRT) with capecitabine. METHODS: Between 2004 and 2008, consecutive patients with clinical tumour category (cT) 3-4 (with a threatened circumferential resection margin or cT3 within 5 cm of the anal verge) or clinical node category 2 rectal cancer were treated with preoperative CRT (25 × 2 Gy, capecitabine 825 mg/m(2) twice daily, days 1-33). TME followed 6 weeks later. Toxicity was scored according to the Common Terminology Criteria (version 3.0) and Radiation Therapy Oncology Group scoring systems. Treatment-related surgical complications were evaluated for up to 30 days after discharge from hospital using the modified Clavien-Dindo classification. RESULTS: Some 147 patients were analysed. The mean cumulative dose of capecitabine was 95 per cent and 98·0 per cent of patients received at least 45 Gy. One patient died from sepsis following haematological toxicity. Grade 3-5 toxicity developed in 32 patients (21·8 per cent), especially diarrhoea (10·2 per cent) and radiation dermatitis (11·6 per cent). There were no deaths within 30 days after surgery. Anastomotic leakage and perineal wound complications developed after 13 of 47 low anterior resections and 23 of 62 abdominoperineal resections. Surgical reintervention was required in 30 patients. Twenty-seven patients (19·6 per cent) of 138 patients who had a laparotomy were readmitted within 30 days after initial hospital discharge. CONCLUSION: Preoperative CRT with capecitabine is associated with acceptable acute toxicity, significant surgical morbidity but minimal postoperative mortality.

Daidzein effect on hormone refractory prostate cancer in vitro and in vivo compared to genistein and soy extract: potentiation of radiotherapy.

PURPOSE: Genistein, the major bioactive isoflavone of soybeans, acts as a radiosensitizer for prostate cancer (PCa) both in vitro and in vivo. However, pure genistein promoted increased metastasis to lymph nodes. A mixture of soy isoflavones (genistein, daidzein, glycitein) did not cause increased metastasis, but potentiated radiotherapy. We tested whether daidzein could negate genistein-induced metastasis. METHODS: Mice bearing PC-3 prostate tumors were treated with daidzein, genistein or both, and with tumor irradiation. Primary tumors and metastases were evaluated. The effects of each isoflavone and soy were compared in vitro using PC-3 (AR-) and C4-2B (AR+) androgen-independent PCa cell lines. RESULTS: Daidzein did not increase metastasis to lymph nodes and acted as a radiosensitizer for prostate tumors. Daidzein inhibited cell growth and enhanced radiation in vitro but at doses higher than genistein or soy. Daidzein caused milder effects on inhibition of expression and/or activities of APE1/Ref-1, HIF-1alpha and NF-kappaB in PC-3 and C4-2B cells. CONCLUSIONS: Daidzein could be the component of soy that protects against genistein-induced metastasis. Daidzein inhibited cell growth and synergized with radiation, affecting APE1/Ref-1, NF-kappaB and HIF-1alpha, but at lower levels than genistein and soy, in AR+ and AR- PCa cells, suggesting it is an AR-independent mechanism.

Toxicity and cytopathogenic properties toward human melanoma cells of activated cancer therapeutics in zebra fish.

There is an increasing body of data showing that activated cancer therapy--the synergistic effect of "preloaded" molecules and a tuned energy source to produce cytopathogenic moieties--is a promising new modality for cancer treatment. The key activated therapies are photodynamic therapy (PDT), which involves the synergy between light and photosensitizer molecules, and ultrasound activated therapy (USAT; also referred to as sonodynamic therapy), which involves the synergy between ultrasound and sonosensitizer molecules. PDT is a well-known activated therapy with roots dating back to 1900. However, minimal data exist on USAT. One reason is the lack of suitable sonosensitizers for clinical USAT use. The authors present both LC(50) toxicity and cancer cell cytotoxicity studies on 2 dual activation agents. These compounds function as both sonosensitizers and photosensitizers, and are referred to as SonneLux agents, designated SF1 and SF2. The sensitizers are derived from chlorophyll and are metal centered porphyrins known to specifically accumulate in hyperproliferating tissue. LC(50) studies on both SF1 and SF2 as determined in zebra fish reveal that both are essentially nontoxic to zebra fish. In the worst case, 5% zebra fish death is noted at the maximum soluble concentration of the sensitizer. In the cytotoxicity studies, melanoma cell line WM-266-4, derived from a metastatic site of a malignant melanoma, was tested against SF1 and SF2. Both sensitizer systems showed marked efficacy in the destruction of the implanted melanoma cells. They show great promise for clinical use in the future.

Phase I study of preoperative radiation therapy with concurrent infusional 5-fluorouracil and oxaliplatin followed by surgery and postoperative 5-fluorouracil plus leucovorin for T3/T4 rectal adenocarcinoma: ECOG E1297.

PURPOSE: Oxaliplatin is a platinum analog and radiosensitizer active in colorectal cancer. We performed a Phase I trial to test the safety and preliminary efficacy of adding oxaliplatin to standard preoperative chemoradiation therapy for rectal cancer. METHODS AND MATERIALS: Eligible patients had T3 to T4 rectal adenocarcinoma. Patients received standard-dose radiation (50.4 Gy for 5.5 weeks) with concurrent infused 5-fluorouracil (5-FU) at 200 mg/m2 per day, 7 days per week. Oxaliplatin was given three times at 14-day intervals at 55, 70, or 85 mg/m2 during the 5.5-week radiation period, before resection. Adjuvant therapy consisted of four cycles of 5-FU (500 mg/m2 per week) with leucovorin (500 mg/m2 per week) given every 6 weeks. The main goals were to identify the maximum tolerated dose of oxaliplatin and the dose-limiting toxicities when given with 5-FU and RT. Secondary goals were to determine resectability, pathologic response, sphincter preservation, and overall survival rates. RESULTS: Twenty-one patients were enrolled, 5 at the 55 mg/m2 oxaliplatin dose level, 5 at 70 mg/m2, and 11 at 85 mg/m2. All patients were able to complete the preoperative chemoradiation regimen with no dose adjustments. No dose-limiting toxicities or differences in the type or extent of toxicity were noted among the groups. Nineteen patients underwent surgery (three abdominopelvic resections and 16 low anterior resections), for an 84% sphincter preservation rate. The pathologic complete response rate was 26% (5 patients), and minimal microscopic residual tumor was found in 21% (4 additional patients). CONCLUSIONS: Oxaliplatin was well tolerated at 85 mg/m2 given every 2 weeks in combination with standard preoperative chemoradiation for rectal cancer. The rates of major pathologic response and sphincter preservation are promising.

Severe reversible toxic encephalopathy induced by cisplatin in a patient with cervical carcinoma receiving combined radiochemotherapy.

CASE REPORT: A 45-year-old patient with cervix carcinoma received combined radiochemotherapy including cisplatin. After a cumulative dose of 240 mg/m(2) the patient suddenly became somnolent and developed a severe tetraparesis and generalized seizures. After ruling out intracranial bleeding, cerebral metastases as well as infectious and metabolic causes of this condition, a severe toxic encephalopathy was diagnosed based on the clinical findings and MRI scans. After symptomatic treatment on the intensive care unit all symptoms were completely reversible. CONCLUSION: Toxic encephalopathy is a rare but dramatic complication of various cytostatic drugs. With the widespread use of cisplatin this rare disorder should be kept in mind.

Can dietary furanocoumarin ingestion enhance the erythemal response during high-dose UVA1 therapy?

As phototoxic skin reactions caused by psoralen are induced by wavelengths within the UVA1 spectrum, we assessed the potential of the small amount of psoralen in a normal diet to provoke phototoxicity in volunteers with skin types I and II. Threshold erythema was unaffected by ingestion of a 200-g portion of parsnip.

Preclinical safety and antitumor efficacy of insulin combined with irradiation.

BACKGROUND AND PURPOSE: We have previously reported that insulin significantly enhances tumor oxygenation (pO(2)) and increases radiation-induced tumor regrowth delay in experimental models. Considering the large radiosensitizing effect, clinical trials might be envisioned. The aim of the present pre-clinical study was to obtain a more complete set of safety and efficacy data which would further justify the commencement of such clinical trials. MATERIAL AND METHODS: Toxicity on normal (early and late-responding) tissues was measured by the intestinal crypt regeneration assay and the late leg contracture assay. Efficacy in terms of enhancement of pO(2) (measured by in vivo EPR oximetry) and increase in radiation-induced tumor regrowth delay was evaluated with a dose-response study on mice bearing FSaII fibrosarcoma. RESULTS: The effect on regrowth delay was directly correlated with the effect on the tumor pO(2), with a maximal effect using 400 mU kg(-1) insulin. Importantly, there was no increase in the radiation toxicity for normal tissues. Finally, we found that the hypoglycaemia induced by insulin can be corrected by simultaneous glucose infusion without modification of efficacy. CONCLUSION: Insulin here demonstrated a therapeutic gain and a lack of toxicity to normal tissues. The results of this study fully justify further larger preclinical assays such as the use of fractionated irradiation and a tumor control dose assay, before determining the utility of insulin as a radiosensitizer for human patients in the clinic.

A phase I study to study arsenic trioxide with radiation and hyperthermia in advanced head and neck cancer.

PURPOSE: Arsenic trioxide [ATO] is a pluripotent drug with potentials to have pro-oxidant, angiogenesis inhibitor, flow inhibitor and radiation sensitizer properties. METHODS: The present study is a Phase I trial to assess the safety of ATO in advanced or recurrent head and neck cancer treated with radiation and hyperthermia. Patients received ATO at 10, 20 and 30 mg per week a day prior to hyperthermia. RESULTS: It was assumed that vascular collapse would be complete by 24 h. Administration of ATO at 20 mg was safe with no toxicity due to ATO. No amplification of toxicities due to radiation or hyperthermia was evident. Patients without prior treatment showed better response. A total of 11 patients were included in this Phase I study. CONCLUSIONS: Patients who received 30 mg of ATO weekly showed non-serious acute toxicities. No further escalation of dose was attempted.

Reduction of radiochemotherapy-induced early oral mucositis by recombinant human keratinocyte growth factor (palifermin): experimental studies in mice.

PURPOSE: To study the effect of recombinant human keratinocyte growth factor (rHuKGF or palifermin) on oral mucositis induced by radiochemotherapy in a mouse model. METHODS AND MATERIALS: Cis-diamminedichloroplatinum (cisplatin) and/or 5-fluorouracil were given before single dose irradiation, combined with palifermin before or after the treatment, or both. Daily fractionated irradiation for 2 weeks was followed by graded test doses. With additional chemotherapy in Week 1, palifermin was given before radiotherapy and at the end of the first week, or additionally at the end of Week 2. Radiochemotherapy in Week 2 was combined with palifermin at the end of Weeks 1 and 2, Weeks 1, 2, and 3, or additionally before radiotherapy. Ulceration of mouse tongue mucosa was analyzed as the endpoint. RESULTS: The dose associated with ulcer induction in 50% of the mice (ED(50)) for single-dose irradiation was 11.5 +/- 0.7 Gy. Palifermin increased the ED(50) to about 19 Gy in all protocols tested. Similar values were observed when chemotherapy was added before irradiation. With fractionated irradiation, palifermin increased the ED(50) for test irradiation from 5.7 +/- 1.5 Gy to 12-15 Gy, depending on the administration protocol. With chemotherapy in Week 1, two palifermin injections had no significant effect, but a third injection increased the ED(50) to 13 Gy. With chemotherapy in Week 2, all palifermin protocols resulted in ED(50) values of 13-14 Gy. CONCLUSION: A marked increase in oral mucosal radiation tolerance by palifermin was found, which was preserved in combinations with chemotherapy using cisplatin and/or 5-fluorouracil.

Efaproxiral: a novel radiation sensitiser.

Efaproxiral (RSR13) is a synthetic allosteric modifier of haemoglobin that reduces its oxygen binding affinity. By facilitating the release of oxygen from haemoglobin, efaproxiral causes an increase in whole blood P 50 (partial pressure of oxygen which results in 50% haemoglobin saturation) and an increase in the PO2 (partial pressure of oxygen) in the tissue. The therapeutic strategy of enhancing oxygen unloading from haemoglobin to tissue emulates and amplifies physiological tissue oxygenation and can enhance the oxygenation of hypoxic tumours. Since hypoxia is known to decrease the effectiveness of radiation therapy, the use of efaproxiral as a radiation sensitiser may be advantageous. Unlike previous radiation sensitisers, efaproxiral does not need to enter the cancer cells to increase radiosensitivity. Phase I-III trial data have defined the safety profile and dosing of the drug, with the potential benefit for extended survival.

The ultraviolet fingerprint dominates the mutational spectrum of the p53 and Ha-ras genes in psoralen + ultraviolet A keratoses from psoriasis patients.

Psoriasis patients exposed to high cumulative doses of psoralen + ultraviolet A frequently exhibit so-called "psoralen + ultraviolet A keratoses" (i.e., hyperkeratotic lesions with varying degrees of histologic atypia). The exact causes and molecular mechanisms of psoralen + ultraviolet A keratoses however, are not clear. We therefore performed DNA mutational analysis of the tumor suppressor gene p53 (exons in psoralen + ultraviolet A keratoses from 10 long-term psoralen + ultraviolet A-treated psoriasis patients. We detected 39 p53 mutations in 16 of 28 psoralen + ultraviolet A keratoses (57%) and 18 Ha-ras mutations in 11 of 25 psoralen + ultraviolet A keratoses (44%). Of the 39 p53 mutations and 18 Ha-ras mutations, 22 (56%) and 13 (72%), respectively, were of the ultraviolet fingerprint type (C-->T or CC-->TT transitions at dipyrimidine sites); 13 (33%) and two (11%), respectively, occurred at potential psoralen-binding sites (5'-TpA, 5'-TpG, or 5'-TpT DNA sequences) and were potentially psoralen + ultraviolet A induced; two (5%) and three (17%), respectively, were of ambiguous origin (ultraviolet and/or psoralen + ultraviolet A); and two (5%) and none (0%), respectively, were of the "other" type, respectively. We conclude that (1) the frequent mutation of p53 and Ha-ras may play a key part in the formation of at least some psoralen + ultraviolet A keratoses; (2) environmental and/or therapeutic ultraviolet exposure may be a major cause of psoralen + ultraviolet A keratosis as most Ha-ras and p53 mutations are induced by ultraviolet light; and (3) psoralen + ultraviolet A itself plays a smaller, though direct, role in causing these mutations.