The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers.

BACKGROUND: The sap from Euphorbia peplus, commonly known as petty spurge in the U.K. or radium weed in Australia, has been used as a traditional treatment for a number of cancers. OBJECTIVE: To determine the effectiveness of E. peplus sap in a phase I/II clinical study for the topical treatment of basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and intraepidermal carcinomas (IEC). METHODS: Thirty-six patients, who had refused, failed or were unsuitable for conventional treatment, were enrolled in a phase I/II clinical study. A total of 48 skin cancer lesions were treated topically with 100-300 µL of E. peplus sap once daily for 3 days. RESULTS: The complete clinical response rates at 1 month were 82% (n = 28) for BCC, 94% (n = 16) for IEC and 75% (n = 4) for SCC. After a mean follow-up of 15 months these rates were 57%, 75% and 50%, respectively. For superficial lesions < 16 mm, the response rates after follow-up were 100% for IEC (n = 10) and 78% for BCC (n = 9). CONCLUSIONS: The clinical responses for these relatively unfavourable lesions (43% had failed previous treatments, 35% were situated in the head and neck region and 30% were > 2 cm in diameter), are comparable with existing nonsurgical treatments. An active ingredient of E. peplus sap has been identified as ingenol mebutate (PEP005). This clinical study affirms community experience with E. peplus sap, and supports further clinical development of PEP005 for the treatment of BCC, SCC and IEC.

A phase I study of moderate-dose radiation therapy and weekly gemcitabine in patients with locally advanced non-small cell lung cancer not suitable for radical chemoradiation therapy.

AIMS: To describe the toxicity and response seen in patients receiving moderate-dose radiation therapy with concurrent weekly low-dose gemcitabine in the management of locally advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Eighteen patients with confirmed NSCLC were enrolled over a 17-month period from August 2000 until January 2002. All had localised disease but were considered unsuitable for curative therapy. Radiation therapy was given to a dose of 30 Gy in 15 fractions over 3 weeks. Gemcitabine was given weekly before and within 3 h of fractions 1, 6 and 11. The study was designed as a dose-escalation study, commencing at 100 mg/m2 and increasing at levels of 50 mg/m2, until the maximum tolerated dose (MTD) was reached. RESULTS: The MTD was regarded as being 150 mg/m2. The major acute toxicity observed was oesophagitis. Skin reactions were also reported. The overall response rate in all patients was 88%, with 44% achieving a complete response. CONCLUSION: The combination of gemcitabine and moderate-dose radiation therapy is feasible, and offers low toxicity and excellent response rates in patients with localised NSCLC not suitable for high-dose therapy.

Radiation therapy following nodal surgery for melanoma: an analysis of late toxicity.

BACKGROUND: The role of adjuvant radiation therapy following resection of malignant melanoma involving regional lymph nodes remains controversial. There is no published randomized trial comparing surgery alone to surgery with postoperative radiation therapy that shows a benefit in terms of local control. Some retrospective studies, however, suggest that radiation given postoperatively reduces local recurrence. One of the obstacles to patients routinely being offered radiation therapy is the concern over the added late toxicity that may occur. The present article is a report of the first 130 patients of a prospective phase II multicentre study in Australia and New Zealand. METHODS: The study was aimed at patients who had had a resection of melanoma in regional nodes or in a regional node basin. The patients were given adjuvant radiation therapy to a recommended dose of 48 Gy in 20 fractions over 4 weeks using accepted radiation techniques for each of the major node sites. This report describes the late toxicity of the treatment received by these patients. RESULTS: The results of late toxicity experienced in the study were acceptable. CONCLUSION: The regimen of radiation therapy used could form the basis for the treatment arm of a randomized trial.

CDKN2A is not the principal target of deletions on the short arm of chromosome 9 in neuroendocrine (Merkel cell) carcinoma of the skin.

The majority of small-cell lung cancers (SCLCs) express p16 but not pRb. Given our previous study showing loss of pRb in Merkel cell carcinoma (MCC)/neuroendocrine carcinoma of the skin and the clinicopathological similarities between SCLC and MCC, we wished to determine if this was also the case in MCC. Twenty-nine MCC specimens from 23 patients were examined for deletions at 10 loci on 9p and 1 on 9q. No loss of heterozygosity (LOH) was seen in 9 patients including 2 for which tumour and cell line DNAs were examined. Four patients had LOH for all informative loci on 9p. Ten tumours showed more limited regions of loss on 9p, and from these 2 common regions of deletion were determined. Half of all informative cases had LOH at D9S168, the most telomeric marker examined, and 3 specimens showed loss of only D9S168. A second region (IFNA-D9S126) showed LOH in 10 (44%) cases, and case MCC26 showed LOH for only D9S126, implicating genes centromeric of the CDKN2A locus. No mutations in the coding regions of p16 were seen in 7 cell lines tested, and reactivity to anti-p16 antibody was seen in all 11 tumour specimens examined and in 6 of 7 cell lines from 6 patients. Furthermore, all cell lines examined reacted with anti-p14(ARF) antibody. These results suggest that neither transcript of the CDKN2A locus is the target of deletions on 9p in MCC and imply the existence of tumour-suppressor genes mapping both centromeric and telomeric of this locus.

UVR induction of TGF alpha: a possible autocrine mechanism for the epidermal melanocytic response and for promotion of epidermal carcinogenesis.

The occurrence of the epidermal growth factor homologue, transforming growth factor alpha (TGF alpha), in embryonic and neoplastic tissues suggests that it may be an oncofetal version of epidermal growth factor. A strong case is developing for TGF alpha to have an autocrine mode of action in sustaining the autonomous growth of several types of tumour. We propose that TGF alpha normally has an autocrine role not only in stimulating the growth of some fetal tissues but also with postnatal epidermal cells in response to local stimuli--in particular ultraviolet radiation (UVR). As a first step to test this hypothesis we have checked whether UVR will induce the production of TGF alpha, measured by radioimmunoassay, using a highly specific monoclonal antibody which recognizes native, biologically active human TGF alpha. We found that cultures of normal foreskin melanocytes do not produce detectable amounts of TGF alpha when grown under routine conditions, but, within 12 h of exposure to low doses of short-wavelength UVR, significant quantities of TGF alpha are produced. The UVR-induced TGF alpha is both cell associated and released into the medium of these cultures. Also, UVR has a promoting action on epidermal cells which have been initiated by carcinogenic activity. A significant part of the promoting activity may be due to autocrine stimulation of multiplication of partially transformed epidermal cells. In this regard we found that UVR induced TGF alpha in HeLa cells and all human melanoma lines so far tested. Induction was complete within 24 h of a single exposure. Dose-response curves of TGF alpha induction in a malignant melanoma cell line showed a distinctive peak of factor induced by low (2 J/m2) doses of UVR. Higher doses which inhibit [3H]thymidine incorporation resulted in lower levels of induced TGF alpha. These findings are consistent with the participation of TGF alpha as an autocrine mediator of UVR-induced tumour promotion, as well as cell multiplication, in sun-exposed skin.

Potentiation of anchorage-independent colony formation by sodium polyanethol sulphonate.

Sodium polyanethol sulphonate (SPS) when incorporated into rat erythrocyte lysate (REL) containing semi-solid agar medium at 1 mg ml-1. markedly enhanced colony formation by a number of anchorage-independent cell lines. REL usually needed to be included for the expression of SPS induced potentiation as in its absence SPS was generally cytotoxic. Studies suggested that SPS reduced the lag prior to colony initiation resulting in the earlier appearance of colonies and in a higher cloning efficiency. The effectiveness of SPS in potentiating colony formation by responsive cell lines was markedly influenced by the species of serum and to a lesser extent by differences between individual batches. Enhancement by SPS was greater with poorer foetal calf serum (FCS) batches than with better. This effect may have been partly due to SPS interfering with the action of a growth inhibiting serum component, possibly a lipoprotein. Studies in which delipidated FCS was substituted for normal FCS suggested that SPS was also able to compensate for the lack of a growth-promoting lipid component. Binding studies showed that initially 125I-SPS bound equally well at 4 degrees C and 37 degrees C with continued labelling occurring only at 37 degrees C. Autoradiography of cells labelled at 37 degrees C for 24 h revealed the presence of intracytoplasmic 125I-SPS.