Systemic targeted alpha radiotherapy for cancer

Abstract

Background: The fundamental principles of internal targeted alpha therapy forcancer were established many decades ago.The high linear energy transfer (LET) ofalpha radiation to the targeted cancer cellscauses double strand breaks in DNA. Atthe same time, the short range radiation spares adjacent normal tissues. This targeted approach complements conventional external beam radiotherapy and chemotherapy. Such therapies fail on several fronts, such as lack of control of some primary cancers (e.g. glioblastoma multiforme) and to inhibit the development of lethal metastaticcancer after successful treatment of the primary cancer.

Objective: This review charts the developing role of systemic high LET, internalradiation therapy.

Method: Targeted alpha therapy is a rapidly advancing experimental therapy thatholds promise to deliver high cytotoxicity to targeted cancer cells. Initially thoughtto be indicated for leukemia and micrometastases, there is now evidence that solidtumors can also be regressed.

Results: Alpha therapy may be molecular or physiological in its targeting. Alphaemitting radioisotopes such as Bi-212, Bi-213, At-211 and Ac-225 are used to labelmonoclonal antibodies or proteins that target specific cancer cells. Alternatively, Radium-233 is used for palliative therapy of breast and prostate cancers because of its bone seeking properties.

Conclusion: Preclinical studies and clinical trials of alpha therapy are discussedfor leukemia, lymphoma, melanoma, glioblastoma multiforme, bone metastases, ovarian cancer, pancreatic cancer and other cancers.

Keywords: Clinical trials; In vitro; In vivo; Lekaemia; Melanoma; Prostate cancer; Radioisotopes; Systemic cancers; Targeted alpha therapy.

Figure 1

Therapeutic Efficacy: The effect of a single intra-peritoneal injection of ²¹³Bi-PAI2 on subcutaneous CFPAC-1 human pancreatic cancer xenografts in nude mice. Single i.p injections of 111, 222, 333MBq/kg of ²¹³Bi-PAI2; 333 MBq/kg of ²¹³Bi-BSA (non-targeted hot control) and PAI-2 with no alpha conjugate (cold control) were given two days post-inoculation.

Figure 2

Uptake if the AIC as a function of time in bone marrow and liver. Saturation occurs within 10 minutes post-injection.

Figure 3

20 of 21 melanomas completely regressed after systemic TAT. The initial sizes of the larger tumours are shown as blue rings. Post-TAT tumour beds revealed a complete absence of viable melanoma cells.