The production of single strand cleavage in covalently-closed circular-DNA by the antitumour agent streptonigrin (reduced in situ by NADH) is demonstrated using the ethidium bromide fluorescence assay described previously. The degradation dependent on oxygen is completely inhibited by superoxide dismutase (EC 1.15.1.1) suggesting the intermediacy of the superoxide radical anion in the degradation. However similar complete inhibition of DNA strand breakage by catalase (EC 1.11.1.6) indicates that the hydroxyl radical (formed by interaction of superoxide with hydrogen peroxide) is the primary reactive species. Cupric ion stimulates the cleavage reaction and cobaltous ion has no effect in keeping with model studies using quinolinequinones.

Photodynamic therapy relies on the selective accumulation of photosensitizers within neoplastic tissue, followed by light activation to generate cytotoxic singlet oxygen. At present, PhotofrinTM, a preparation of hematoporphyrin derivatives (HPD) with the bulk of the porphyrin monomers removed, is the only clinically approved photosensitizer. Intravesical administration of Photofrin or HPD has failed to photosensitize bladder tumors. Bladder cancer is the second most common genitourinary malignancy. In 1994 there were an estimated 51 200 cases of bladder cancer with 10 600 deaths in the United States. The predominant histopathology is transitional cell carcinoma, occurring in 90–95% of these cases. Most patients (85%) have superficial disease at the time of initial diagnosis. Superficial bladder cancer is defined as disease involving the mucosa with carcinoma in situ or papillary lesions and invasion limited to submucosa. To address these limitations we have been conducting preclinical studies with perylenequinones (PQs). The majority of our effort has focused on developing and characterizing derivatives of PQs. Following site-directed modifications, we have identified certain congeners that warrant further preclinical development. These compounds are monomeric and do not effect cutaneous photosensitization beyond 24 h. With clinically relevant drug and light doses we have cured >90% of experimental subcutaneous murine tumors. Keywords: photodynamic therapy, perylenequinones, photobiology, photochemistry.

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Podophyllotoxin is a natural product isolated from Podophyllum peltatum and Podophyllum emodi and has long been known to possess medicinal properties. Etoposide (VP-16), a podophyllotoxin derivative, is currently in clinical use in the treatment of many cancers, particularly small cell lung carcinoma and testicular cancer. This compound arrests cell growth by inhibiting DNA tope­ isomerase II, which causes double strand breaks in DNA. VP-16 does not inhibit tubulin polymerization, however, its parent compound, podophyllotoxin, which has no inhibitory activity against DNA topoisomerase II, is a potent inhibitor of microtubule assembly. 111 addition to these two mechanisms of action, an unknown third mechanism of action has also been proposed for some of the recent modifications of podophyllotoxins. Owing to its severe toxic side effects a number of modifications have been done on podophyllotoxin structure. Some of the congeners exhibited potent antitumor actiivity, of which etoposide and teniposide are in clinical use, NK 611 is in phase II clinical trials and many compounds are in the same line. Recent developments on podophyllotoxins have led structure-activity correlations which have assisted in the design and synthesis of new podophyllotoxin derivatives of potential antitumor activity. Modification of the A-ring gave compounds having significant activity but less than that of etoposide, whereas modification of the B-ring resulted in the loss of activity. One of the modifications in the D-ring produced GP-11 which is almost equipotent with etoposide. E-ring oxygenation did not affect the DNA cleavage which led to the postulation of the third mechanism of action. It has also been observed that free rotation of E-ring is necessary for the antitumor activity. The C4-substituted aglycones have a significant place in these recent developments. Epipodophyllotoxin conjugates with DNA cleaving agents such as distamycin increased the number of sites of cleavage. The substitution of a glycosidic moiety with arylamines produced enhanced activity. Modification in the sugar ring resulted in the development of the agent, NK 611 which is in clinical trial at present. This article review, the progress of podophyllotoxins from its early applications in folk medicine to the most recent modifications and the mechanism(s) of action, pharmacology and the structure-activity relationships.