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New agents directed against molecular targets have now been tested in large prospectively randomized clinical trials for patients with untreated advanced non-small cell lung cancer (NSCLC). The trials have included small molecule inhibitors of receptor tyrosine kinases (gefitinib and erlontinib), monoclonal antibodies directed against either the ligands (bevicizumab against vascular endothelial growth factor) or their receptors (trastuzumab against ErbB2) and antisense nucleotides directed against mRNA coding for molecular targets (ISIS 3521 against protein kinase C alpha). The largest mature trials have included agents directed against ErbB1 (epidermal growth factor receptor). Two different small molecule inhibitors of erbB1 (gefitinib and erlontinib) and have been tested in 4 large international randomized trials. Two trials treated patients with advanced NSCLC with either gemcitabine and cisplatin or the same chemotherapy drugs combined with two different doses of gefitinib or one dose of erlontinib (INTACT 1 and TALENT). The other two trials treated patients with advanced NSCLC with either paclitaxel and carboplatin or the same chemotherapy drugs combined with either one of two doses of gefitinib or a single dose of erlontinib (INTACT 2 or TRIBUTE respectively). The results of INTACT 1 and INTACT2 showed no significant difference in survival between those treated with conventional combination chemotherapy and those treated with the same chemotherapy plus gefitinib. The results of the TRIBUTE and TALENT studies showed their primary endpoints of improving overall survival were not met. The monoclonal antibody, bevacizumab, is being tested in an ongoing clinical trial. The trial will compare the outcome of patients with untreated advanced adenocarcinoma of the lung treated with paclitaxel plus carboplatin to those treated with the same chemotherapy drugs plus bevacizumab. The results are scheduled to be available in 2005–2006. Although the initial trials adding newly developed molecular targeted agents have not shown initial success when added to conventional combination chemotherapy, further clinical trials are needed to ultimately define their role in the treatment of non-small cell lung cancer.

Trans to cis photoisomerization of epidermal urocanic acid (UCA) has been proposed as a primary event in UV-induced immunosuppression. 8-Methoxypsoralen (8-MOP) in combination with UVA radiation (PUVA) is used for photochemotherapy of several immunologicaly based skin disorders, and PUVA is known to cause immunosuppression. We examined the photointeraction of 8-MOP and other skin photosensitizing drugs (amiodarone, ciprofloxacin, doxycycline and ketoprofen) with trans-UCA in vitro. In oxic condition 8-MOP did not enhance the ability of radiation from standard PUVA fluorescent sources (0.2% radiation below 320 nm) to produce cis-UCA. When oxygen was removed, some 8-MOP photosensitization could be detected. 8-MOP, ciprofloxacin and ketoprofen also enhanced inefficient UCA photoisomerization by radiation from a filtered tungsten halogen source (0.2% radiation below 320 nm). 8-MOP photosensitization is essential for radiation from PUVA tubes to have a therapeutic or immunosuppressive effect. We have shown in vitro that 8-MOP does not enhance cis-UCA production by this source. Extrapolation of our data to the in vivo situation suggests that UCA may not be involved in either the therapeutic or the immunosuppressive effect of PUVA.

Forty-five patients with extensive chronic plaque or guttate psoriasis were treated with either narrowband (TL-01) phototherapy, etretinate TL-01 combination therapy (re-TL-01) or etretinate and PUVA (re-PUVA) (15 patients in each group). Re-PUVA was the most effective therapy with 100% satisfactory clearance rate. TL-01 monotherapy had an 80% success rate; the relapse rate compared favourably with re-PUVA (50% in remission after 6 months). In the etretinate-TL-01 group, there was a 93% success rate and a one-third reduction in the total irradiation dose (8.0 J/cm2 vs. 12.7 J/cm2) but the relapse rate was higher, only 33% remaining in remission after 6 months.

Ciprofloxacin is one of the new series of broad-spectrum antibiotic quinolones, chemically related to nalidixic acid and which may, therefore, induce photosensitization of human skin. Three in vitro tests for phototoxicity: the destruction of histidine, killing of mouse peritoneal macrophages and inhibition of PHA-stimulated DNA synthesis in human lymphocytes have demonstrated this photosensitizing potential with UVA irradiation at an order of magnitude lower than that for nalidixic acid. The Candida albicans test and photohaemolysis were negative. Controlled irradiation monochromator phototesting of 12 subjects, before, during and after taking ciprofloxacin showed subclinical photosensitivity with significantly lowered minimal 24 h erythema doses at 335 +/- 30 nm, 365 +/- 30 nm and 400 +/- 30 nm but not at 305 +/- 5 nm or above 400 +/- 30 nm.

The phototoxic potential of several non-steroidal anti-inflammatory drugs and quinolone antibiotics was assessed using the photohaemolysis assay. In this system, human erythrocytes are irradiated (UVA radiation 320-400 nm) from below in the presence of suspected photosensitizers. Photohaemolysis with ketoprofen, tiaprofenic acid or nalidixic acid was initially concentration dependent, but photohaemolysis apparently decreased at higher drug concentrations. As erythrocytes were irradiated from below any optical screening at high drug concentrations was discounted. Other phototoxic drugs can oxidize haemoglobin to methaemoglobin resulting in a decrease in absorption and an artificially lowered photohaemolysis level. However, in the present experiments, the use of Drabkin's solution overcame this effect as haemoglobin and most of its oxidized derivatives were converted into a single derivative, namely cyanmethaemoglobin. Further possibilities are that photosensitized damage to haemoglobin results in the formation of intracellular Heinz bodies and/or bleaching of released haemoglobin. The latter hypothesis was tested by irradiating free haemoglobin in the presence of drugs. The results suggested that certain phototoxic agents cause 'bleaching' of the haemoglobin and formation of a derivative that fails to react with Drabkin's solution. If only high concentrations of these drugs are used in the photohaemolysis assay, this increases the risk of false negative results. It is therefore suggested that both photohaemolysis and photosensitized 'bleaching' of haemoglobin should be investigated when using this assay for screening drug phototoxicity.

Cutaneous photosensitivity reactions are a consistent although uncommon feature of the fluoroquinolone group of antibiotics, which are related to nalidixic acid. Objective laboratory and clinical data are now routinely required by regulatory bodies for new drugs suspected of being photosensitizers, but no clear recommendations exist. A series of in vitro tests ranging in complexity revealed a UVA-dependent phototoxic potential for the fluoroquinolone norfloxacin similar to that for ciprofloxacin, and less than that of nalidixic acid. Controlled monochromator phototesting, designed to reveal the clinical characteristics, wavelength dependence and severity of cutaneous reactions in normal subjects showed both norfloxacin and ciprofloxacin to have a weak phototoxic potential which clears within 4 weeks of stopping the drug. UVA wavelengths (335 +/- 30 nm; 365 +/- 30 nm) appear most responsible for producing an asymptomatic erythema which is maximal at 24 h. The clinical study differs from those used previously in being blind, containing positive and negative controls, and phototesting after cessation of drug intake. The methodology has the anticipated limitation of failing to detect idiosyncratic photosensitivity responses.

Anecdotal reports suggest that the dihydropyridine calcium antagonist, nifedipine (NIF), may be phototoxic in human skin. We have studied NIF phototoxicity in vitro using UVA fluorescent tubes (Sylvania PUVA). NIF was phototoxic to Candida albicans and induced photohaemolysis both with NIF present during irradiation and with pre-irradiated drug. In V79 hamster fibroblasts, NIF (10 micrograms ml-1) was phototoxic MTT assay) 24 h after irradiation (0-112 kJ m-2); at 7.5 kJ m-2, about 70% of cells were damaged whilst at 37.5 kJ m-2, only about 45% of cells were damaged. A similar pattern was seen with pre-irradiated NIF. Absorption spectroscopy showed that the NIF absorption maximum (Amax approximately 340 nm) blue-shifted to 314 nm at low UVA doses (7.5 kJ m-2 or less) and red-shifted to 345 nm at higher doses (isosbestic point, 325 nm). Thin layer chromatography of irradiated NIF showed a single photoproduct (PP1; Amax approximately 314 nm) formed at 7.5 kJ m-2 or less which disappeared at higher UVA doses to give further photoproducts. PP1 was highly dark toxic to V79 cells (50% damage at about 5 micrograms ml-1) but PP1 pre-irradiated with UVA was non-toxic. Preliminary gas chromatography-mass spectroscopy studies suggest that PP1 is the nitroso derivative of NIF. These results indicate that NIF phototoxicity in vitro is partially mediated by initial formation of a toxic photoproduct (PP1) but, paradoxically, subsequent UVA irradiation may reduce phototoxicity. The NIF concentrations required to induce in vitro phototoxicity are much greater than therapeutic plasma levels. Unless there is skin accumulation of NIF or PP1, our in vitro results suggest that NIF may not be an important skin-photosensitizing agent in vivo.

Solutions of ciprofloxacin were irradiated with different wavebands of ultraviolet and visible radiation and the antibiotic activity of the drug was determined against Escherichia coli. A wavelength dependent loss of antibiotic activity was found with maximal effect around 320 nm; no effect occurred with visible irradiation. The degree of the decrease in activity with longer wavelength ultraviolet (UVA) radiation was sufficient to indicate that human exposure to sunlight through window glass (greater than 320 nm) or UVA from tanning sunbeds may result in a significant reduction in both cutaneous and circulating levels of ciprofloxacin.

SUMMARY A study of the abnormal sunlight response seen in nine patients taking benoxaprofen showed that the action spectrum was between 310 and 325 nm, which is similar to the drug's absorption spectrum. In vitro studies using three separate methods indicated that benoxaprofen has a powerful phototoxic action which may be directed mainly against cellular membranes.

Abnormal cutaneous photosensitivity is included among a number of more common side effects of tretinoin (Fig. 1; al l trans-ret inoic acid) (Pedace and Stoughton, 1971; Papa et al., 1975). The related synthetic retinoids, etretinate (Tigason) and isotretinoin (Roaccutane) (Fig. 1) may well produce a similar photosensitization. While photosensitivity is frequently listed as an adverse effect of isotretinoin, reports in the literature are contradictory. An increased susceptibility to sunburn reactions has been stated to occur in 5-12% of patients (Angel, 1983; Strauss et al., 1984) but the work of others has failed to detect this problem (Diffey et al., 1985). A single case report of clinical photosensitivity by McCormack and Turner (1983) described burning erythema of sun-exposed sites which was thought to be phototoxic in origin. Phototesting a group of subjects taking isotretinoin proved negative (Diffey et al., 1985). Etretinate has also been reported as causing sunburn reactions in 7-9% of patients (Grekin et al., 1984). Two early studies failed to produce evidence of an abnormal response to sunlight in subjects taking the drug (Ippen et al., 1978; Goerz and Orfanos, 1978) but case reports continue to appear in the literature (Collins et al., 1986).

Human lymphocytes exposed to the effects of long wave UV radiation in the presence of 8-methoxypsoralen prior to stimulation by PHA show dose related sister chromatid exchanges after 2 replication cycles in vitro. This has implications for interpreting the processes involved and for monitoring DNA damaging agents in vivo.

Quinine induced photosensitivity, an infrequently described adverse effect, is reported in four patients. The clinical presentation and distribution was that of a light exposed site eruption characterized by oedema and erythema in three patients, and by lichen planus in the fourth. Monochromator phototesting demonstrated abnormal delayed erythema responses in the UVB, UVA and visible wavebands. The clinical features suggested a phototoxic effect but laboratory studies indicated that the molecular mechanisms involved are unusual. Clinical and phototest evidence of abnormal photosensitivity persisted for some months after stopping quinine. Broad spectrum sunscreens are advised for the management of such patients and, where possible, cessation of quinine administration.

Six subjects taking isotretinoin were studied, none of whom had clinical or phototest evidence of photosensitivity. Of nine subjects taking etretinate, one had convincing clinical photosensitivity consisting of a burning erythema on sunlight exposure. His phototesting results showed a marked abnormality from 300 +/- 5 nm to 365 +/- 30 nm which returned close to normal limits within one month of stopping therapy. Although clinically normal, another subject taking etretinate had similar phototest evidence of abnormal photosensitivity. In vitro photohaemolysis studies demonstrated that tretinoin (all-trans-retinoic acid) and isotretinoin have a potential, while etretinate has none. However, the major metabolite of etretinate (Ro 10-1670) had a phototoxic potential greater than that of tretinoin. The apparently low incidence of photosensitivity suggests that an idiosyncrasy is responsible, perhaps due to a disorder of pharmacokinetics or metabolism. Clinical cases should use appropriate photoprotection against UVB and UVA wavebands.