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ICAAC 2010: Experimental Drug LMV-601 Inhibits HPV Replication and Abnormal Cell Growth in Laboratory Study

Lumavita's LMV-601, an investigational PC-PLC inhibitor, reduced expression of high-risk human papillomavirus (HPV) types 16, 18, and 31, and over time improved pre-cancerous cervical cell abnormalities in a laboratory study, researchers reported at the 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010) last month in Boston.

Human papillomavirus can cause abnormal cell growth ranging from warts to cervical or anal cancer. Numerous studies have shown that cervical and anal dysplasia, or pre-cancerous cell changes, are more common among HIV positive compared with HIV negative people.

The phosphatidylcholine-specific phospholipase or PC-PLC enzyme plays a role in the cell division cycle, and agents that inhibit PC-PLC may therefore potentially interrupt abnormal cell proliferation.

Eberhard Amtmann 
from the German Cancer Research Center
in Heidelberg and colleagues looked at the effect of the experimental PC-PLC inhibitor LMV-601 on cultured human cervical cancer cells.

After infection, HPV genetic material (DNA) is integrated into the chromosome of a host cell, the researchers explained in a press release issued by ICAAC. As a consequence, a specific part of the viral genetic sequence -- known as an oncogene -- transforms normal cervical cells into immortalized cells that multiply indefinitely. Normal cells have limited growth potential; being immortal is one of the prerequisites for becoming a cancer cell.

The investigators previously showed in another lab study that LMV-601 inhibits transcription of the HPV-31 genome in pre-malignant transformed human cervical epithelial cells. HPV DNA replication was stopped, and with prolonged treatment the cells lost their transformed appearance and finally became senescent, or exhausted, and stopped dividing.

In the present study, the team investigated whether LMV-601 is also active against other cancer-causing HPV types. This in vitro analysis used CaSki (infected with HPV-16) and HeLa (infected with HPV-18) cells derived from patients with high-risk HPV who developed cervical cancer. HPV types 16 and 18 cause 75% of cervical cancer cases in North America, according to the researchers.

When the human cancer cells were treated with LMV-601 in a culture plate, the investigators observed the following:

·      Virus expression was halted;

·      Growth and multiplication of cancer cells was stopped;

·      The cancerous cells grew like normal cells.

In more detail:

·      Expression of the viral E7 gene, which is responsible for transforming normal cells into cancer cells, was reduced by more than 1000-fold after 6 days of treatment.

·      Treatment of HPV-16 or HPV-18 infected cancer cells for 3 days led to increased levels of a cellular tumor suppressor gene product, the retinoblastoma (Rb) gene, an important step in inducing death of malignant cells.

·      The number of HPV-infected cancer cells started to decrease after 9 days of treatment with LMV-601, showing that the transformed cells lose their capacity to multiply and will "die out."

·      After 10 days of treatment, the beta-galactosidase gene -- an indicator of cell senescence -- increased in HPV-infected cell lines, consistent with the observation that immortal malignant cells changed into normal mortal cells.

"The PC-PLC inhibitor LMV-601 is active on at least 3 different high risk HPV types (16, 18 and 31) found in the majority of cervical cancers," the researchers concluded. "With prolonged treatment, HPV transformed pre-malignant and malignant cells become senescent."

LMV-601 does not act on the virus directly, but instead causes an infected cell to block multiplication of the virus, they explained. This mechanism of action should be effective against all HPV types and makes development of viral resistance to the drug "very unlikely."

LMV-601 will be tested in women with early stage cervical cancer in 2011, according to the investigators. If results are promising, "this will be an important step towards the first effective drug treatment of HPV infections," which bear a high risk of progressing to cervical cancer.

Although the researchers did not report results using anal cancer cells, a drug like LMV-601 would be expected to work as well against anal cancer as cervical cancer, both of which are caused by the same high-risk HPV types.

Investigator affiliations: German Cancer Research Center, Heidelberg, Germany; Lumavita AG, Basel, Switzerland; BioSphings AG, Frankfurt, Germany.

10/5/10

Reference

E Amtmann, FK Mayer, H Pink, and others. LMV-601: Effect on HPV-16 and HPV-18 Infected Human Cervical Carcinoma Cells. 50th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2010). Boston, September 12-15, 2010. Abstract F1-1646.

Other Source

ICAAC. New Drug Against HPV Malignancies. Media advisory. September 14, 2010.