Systemic therapy for renal cell carcinoma

Status of new anthrapyrazole and pyrazoloacridine derivatives.

Piroxantrone is an anthrapyrazole compound undergoing phase II testing in a variety of diseases. The anthrapyrazoles are a series of compounds synthesized with the intent of maintaining the broad antitumor activity of anthracyclines, but with lessened cardiac toxicity. The Southwest Oncology Group (SWOG) conducted a phase II trial of piroxantrone in advanced soft tissue sarcoma. Treatment consisted of piroxantrone 150 mg/M2 administered intravenously over 1 hour every 21 days. Twenty-five eligible patients were registered to the trial. Twenty-three patients received treatment and are fully evaluable for response and toxicity. Two partial responses were seen for an overall response rate of 9% (95% confidence limit 1%–28%). Abnormal cardiac ejection fraction occurred in five patients, and fatal congestive heart failure developed in one patient on study. Toxicities other than cardiac were tolerable. Based on the observed response rate and cardiac toxicity, further trials of piroxantrone in the treatment of soft tissue sarcoma do not appear warranted.

Phase II trial of piroxantrone for advanced or metastatic soft tissue sarcomas. A Southwest Oncology Group study.

Publisher Summary A common strategy of anti-neoplastic drug discovery in the past several years has been to discover the way by which an effective anti-cancer agent works and use this knowledge in a mechanism-based drug discovery program to find new structures that work by a similar mechanism but have greater activity and/or fewer side-effects. The majority of this chapter focuses on promising new agents that have entered clinical trial in the past few years, preclinical compounds with a degree of efficacy in animal models that would appear to warrant development to clinical trial, and compounds that demonstrate unique mechanisms or unusual activities in preclinical studies. The exceptional preclinical profiles and apparent clinical efficacy of compounds related to camptothecin has spawned a search for other classes of compounds that produce DNA damage mediated by topoisomerase I. Several clinically useful anti-neoplastic agents inhibit DNA topo II. Among the inhibitors of this important enzyme, three compound classes have shown promise in ongoing clinical trials: anthrapyrazoles, ellipticines, and amonafide. There are a number of agents with either novel or unknown mechanisms of action that are currently being evaluated as anti-cancer agents. Much of the focus in anti-cancer drug discovery has been directed away from agents that kill cells by producing DNA damage and toward modulators of signal transduction pathways that have become unregulated or otherwise aberrant in malignant transformation. Anti-neoplastic agents with completely novel mechanisms of action are the subject of intensive preclinical study and may begin to impact on cancer treatment toward the end of the decade. The anti-cancer agents currently showing promise in clinical trials operate by mechanisms similar to those of the established drugs.

Chapter 18. Antineoplastic Agents

Comparison of the chronic toxicity of piroxantrone, losoxantrone and doxorubicin in spontaneously hypertensive rats

The Southwest Oncology Group (SWOG) studied the response rate and toxicity of piroxantrone (150 mg/m2 q 21 days) in patients with advanced metastatic renal cell carcinoma. Among 32 eligible patients, there were no partial nor complete responses. There were two mixed responses. Significant white cell toxicity, anemia, nausea, and vomiting were observed. Mild or moderate degrees of fever, malaise, and stomatitis occurred. No significant cardiac toxicity was noted. Piroxantrone does not have significant activity as a single agent in advanced renal cell carcinoma.

/pdf/phase-ii-evaluation-of-piroxantrone-in-renal-cell-carcinoma-2z0ngxwzao.pdf

Phase II evaluation of piroxantrone in renal cell carcinoma. A Southwest Oncology Group Study.

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Phase II evaluation of piroxantrone in renal cell carcinoma. A Southwest Oncology Group Study.