Methoxsalen — also called xanthotoxin, marketed under the trade names Oxsoralen, Deltasoralen, Meladinine — is a drug used to treat psoriasis, eczema, vitiligo, and some cutaneous lymphomas in conjunction with exposing the skin to UVA light from lamps or sunlight. Methoxsalen modifies the way skin cells receive the UVA radiation, allegedly clearing up the disease. The dosage comes in 10 mg tablets, which are taken in the amount of 30 mg 75 minutes before a PUVA (psoralen + UVA) light treatment. Chemically, methoxsalen belongs to a class of organic natural molecules known as furanocoumarins. They consist of coumarin annulated with furan. It can also be injected and used topically. The exact mechanism of action of methoxsalen with the epidermal melanocytes and keratinocytes is not known. The best known biochemical reaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and forms covalent bonds with DNA which leads to the formation of both monofunctional (addition to a single strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands of DNA) Reactions with proteins have also been described. Methoxsalen acts as a photosensitizer. Administration of the drug and subsequent exposure to UVA can lead to cell injury. Orally administered methoxsalen reaches the skin via the blood and UVA penetrates well into the skin. If sufficient cell injury occurs in the skin, an inflammatory reaction occurs. The most obvious manifestation of this reaction is delayed erythema, which may not begin for several hours and peaks at 48–72 hours. The inflammation is followed, over several days to weeks, by repair which is manifested by increased melanization of the epidermis and thickening of the stratum corneum. The mechanisms of therapy are not known. In the treatment of vitiligo, it has been suggested that melanocytes in the hair follicle are stimulated to move up the follicle and to repopulate the epidermis. In the treatment of psoriasis, the mechanism is most often assumed to be DNA photodamage and resulting decrease in cell proliferation but other vascular, leukocyte, or cell regulatory mechanisms may also be playing some role. Psoriasis is a hyperproliferative disorder and other agents known to be therapeutic for psoriasis are known to inhibit DNA synthesis. The most commonly reported side effect of methoxsalen alone is nausea, which occurs with approximately 10% of all patients. This effect may be minimized or avoided by instructing the patient to take methoxsalen with milk or food, or to divide the dose into two portions, taken approximately one-half hour apart. Other effects include nervousness, insomnia, and psychological depression.

Pibrozelesin (KW-2189) is a semisynthetic water-soluble derivative of the antineoplastic antibiotic duocarmycin B2. Activated by carboxyl esterase, pibrozelesin alkylates DNA by binding to adenine-thymine (A-T)-rich sequences in the minor groove of DNA, thereby inhibiting DNA replication and inducing apoptosis. KW-2189 induced DNA strand breaks in H69 cells in a concentration-dependent manner. DNA cleavage is one of the major mechanisms of KW-2189-mediated cytotoxicity. KW-2189 showed evidence of anti-tumor activity in hepatocellular carcinoma (HCC). However, because of significant and prolonged hematologic toxicity, when given as a single dose every 6 weeks, further development of this drug in HCC is not possible. Pibrozelesin had been in phase II clinical trial for the treatment of advanced malignant melanoma and advanced renal cell carcinoma. No activity in metastatic renal cell carcinoma was demonstrated and the lack of significant antitumor activity in advanced malignant melanoma treatment was shown.

Mitonafide is a nitro-containing antitumor drug. Mitonafide participated in clinical trials phase II in colorectal cancer patients, however, the results have shown that the drug was not active and induced severe myelotoxicity. Besides, the drug was involved in phase II for the patients with non-small cell lung cancer (NSCLC), where it was not active in spite of the safe administration. Information about the current development of this drug is not available.

Adozelesin (U 73975, adolezesin) is an experimental antitumor drug of the duocarmycin class. Adozelesin is a highly potent alkylating agent that undergoes binding in the minor groove of double-stranded DNA (ds-DNA) at A-T-rich sequences followed by covalent bonding with N-3 of adenine in preferred sequences. Adozelesin is therapeutically active against a broad spectrum of tumours and was in phase II clinical trials with Pharmacia Corporation (now Pfizer) in the US for breast cancer treatment. Phase I and Phase II clinical trials were conducted in 2000s, however, it was found adozelesin had marginal efficacy in the treatment of metastatic breast cancer at the dosage and schedule used.

Crisnatol is a derivative of arylmethylaminopropanediol with significant antineoplastic activity in a variety of murine and human tumor models. Crisnatol functions as a DNA intercalator, with the presence of additional basic amine groups in the sidechain enhancing binding to DNA due to electrostatic interactions. Crisnatol did not show antitumor efficacy in patients with ovarian carcinoma. In another clinical study, 2 of 26 patients with glioma showed complete long-lasting responses to the drug. The dose-limiting side effect was neurotoxicity.

Elinafide (LU 79553) is a bisintercalating naphthalamide and a topoisomerase II inhibitor has demonstrated a higher binding affinity for DNA and significant antitumour efficacy against a panel of established tumour cell lines, including several multidrug resistant-positive sublines. Elinafide had been in phase II clinical trial for the treatment of ovarian cancer and phase I trials for the treatment of various solid tumours. The major haematological toxicities observed were anaemia and neutropenia. The major non-haematological toxicities observed in the 3-weekly schedule were neuro-muscular presenting clinically as a mixed syndrome of severe weakness (sometimes with pain in both legs), myalgia and arthralgia, asthenia/fatigue/malaise. One fatality was considered related to LU 79553, as the patient had fever and neutropenia. Clinical study of this drug candidate was discontinued due to its neuromuscular dose-limiting toxicity.

Nogalamycin is an unusual anthracycline antineoplastic antibiotic isolated from the bacterium Streptomyces nogalater. Nogalamycin intercalates into DNA and interacts with topoisomerase I, thereby inhibiting DNA replication and repair and RNA and protein synthesis. Nogalamycin contains two saccharides. The neutral monosaccharide attaches to the D ring, similar to the aminoglycoside moieties of the doxorubicin class, while the second, basic saccharide attaches to the phenolic group on the A ring in the ortho position to form a unique family of hexacyclic anthracyclines. Nogalamycin is potent antibacterial and antitumor agent. Nogalamycin was markedly cytotoxic in vitro and was active against several tumor systems in vivo.

Bisnafide (previously known as DMP 840), a bis-naphthalimide derivative that was developed by Bristol-Myers Squibb as a potential anticancer agent. Bisnafide acts as DNA intercalator and topo II inhibitor. This drug participated in phase I clinical trials in pediatric patients with refractory solid tumors. However, further, development has been discontinued.

Menogaril is a semisynthetic derivative of the anthracycline antineoplastic antibiotic nogalamycin. Biochemical studies indicated that, in comparison to doxorubicin, menogaril is bound weakly to DNA, inhibits RNA synthesis less, and has different cell cycle phase-specific cytotoxicity. Menogaril acts as a cleavable complex-stabilizing topoisomerase II inhibitor. Menogaril has been studied in the treatment of various cancers.

Losoxantrone is an anthrapyrazole that induces both single and double strand breaks in DNA and is a potent inhibitor of DNA synthesis. The drug is in clinical trials for the treatment of breast cancer and of prostate cancer that is refractory to androgen ablation. Acute toxicity is negligible. Losoxantrone may be less cardiotoxic than doxorubicin. Up to 40% of patients encounter alopecia. 3% of patients develop congestive heart failure. Losoxantrone had been in phase II clinical trial for the treatment of breast and prostate cancer. However, this development was discontinued.